JP5963844B2 - Pyridopyrazine derivatives and uses thereof - Google Patents

Description

  The present invention relates to pyridopyrazine derivatives having novel biological effects and said derivatives for the treatment of physiological and / or pathophysiological conditions mediated and / or regulated by signaling pathways in mammals, especially humans. It relates to the use used for.

The prior art signaling cascade, ras-Raf-Mek-Erk, plays a central role in cell growth, cell proliferation, apoptosis, adhesion, migration and glucose metabolism. Thus, fundamental involvement in the pathogenesis of diseases such as cancer, neurodegeneration and inflammatory diseases has been demonstrated for the ras-Raf-Mek-Erk signaling pathway. Individual components of these signal cascades are therefore important therapeutic attack points for intervention in various disease processes (Weinstein-Oppenheimer CR et al. 2000, Chang F. et al. 2003, Katso R et al 2001 and Lu Y. et al 2003).

  The molecular identification and biological properties of the ras-Raf-Mek-Erk signaling pathway are first described separately below.

  Multiple growth factors, cytokines and oncogenes convert their growth-promoting signals through activation of G protein-coupled ras, which activates serine-threonine kinase Raf and mitogen activation Causes activation of protein kinase kinases 1 and 2 (MAPKK1 / 2 or Mek1 / 2) and phosphorylation and activation of kinases known as extracellular signal-regulated kinases (Erk1 and 2) such as MAPK 1 and 2 . Compared to other signaling pathways, the ras-Raf-Mek-Erk signaling pathway is associated with a number of proto-oncogenes including ligands, tyrosine kinase receptors, G proteins, kinases and nuclear transcription factors. linked. For example, tyrosine kinases such as EGFA (Mendelsohn J. et al., 2000) often constitutively activate signals downstream of ras-Raf-Mek-Erk signals in tumor events caused by overexpression and mutation. Mediates into the pathway. Ras mutations are mutated in 30% of all human tumors (Khleif SN et al., 1999, Marshall C., 1999), with the highest incidence of 90% seen in pancreatic cancer. (Friess H. et al., 1996, Sirivatanauksorn V. et al., 1998). c-Raf has been described for deregulated expression and / or activation in various tumors (Hoshino R. et al., 1999, McPhillips F. et al., 2001). B-Raf point mutants were detected in 66% of all human malignant melanomas, 14% of all ovarian cancers, and 12% of all colon cancers (Davies H. et al., 2002). ). Thus, it is not surprising that Erk1 / 2 is primarily involved in many cellular processes such as cell growth, cell proliferation and cell differentiation (Lewis T.S. et al., 1998, Chang F. et al., 2003).

  Furthermore, members of Raf kinases also have a Mek-Erk-independent anti-apoptotic function, whose molecular steps have not yet been fully described. Ask1, Bcl-2, Akt and Bag1 have been described as possible interaction partners for the Mek-Erk-independent Raf activity (Chen J et al., 2001, Troppmaier J. et al., 2003, Rapp UR et al., 2004, Gotz R. et al., 2005). Currently, both Mek-Erk-dependent and Mek-Erk-independent signaling mechanisms are assumed to control the activation of upstream ras and Raf stimuli.

  Various inhibitors of the individual components of the ras-Raf-Mek-Erk signaling pathway have already been published and patented.

  Current developments in the field of kinase inhibitors, particularly in the ras-Raf-Mek-Erk and PI3K-Akt pathways, are reviewed in HT Arkenau et al, 2011, MS Chapman & JN Miner, 2011 and P. Liu et al, 2009 It is described in. These documents contain an extensive list of published small molecule ras-Raf-Mek-Erk inhibitors and PI3K inhibitors.

  Sorafenib (Bay 43-9006; WO 99/32111, WO 03/068223), a kinase inhibitor approved in 2006, is a serine / threonine kinase such as Raf, VEGFR2 / 3, Flt-3, PDGFR, c-Kit and Shows a relatively non-specific pattern of inhibition of tyrosine kinases as well as other kinases. The inhibitors are of great importance in advanced tumor diseases induced by angiogenesis (eg in renal cell carcinoma) and also in melanomas with high B-Raf mutation rates. Inhibition of kinases in the PI3K-Akt signaling pathway has not been described for Bay 43-9006. Other Raf-specific inhibitors such as PLX-4032 and GSK2118436 (Arkenau H.T. et al, 2011) are currently in clinical evaluation.

  Several Mek1 / 2 inhibitors (AZD-6244, XL-518, GSK1120212, etc.) are currently undergoing clinical trials (reviewed by MS Chapman & JN Miner, 2011). However, for these Mek inhibitors, no interaction with Erk1 or Erk2, any PI3K-Akt signaling pathway inhibitory function, or simultaneous modulation thereof has yet been disclosed.

  The patent specification WO 2009/077766 describes pyrido [2,3-b] pyrazine as a RAF inhibitor.

  Furthermore, the patent specifications WO 2008/040820, WO 2008/009908 and WO 2005/123733 describe pyrido [2,3-b] pyrazine as an agrochemical fungicide and herbicide, respectively.

  KR 2008004646, a Korean invention, describes 2-alkenyloxy-3-ethynylpyrido [2,3-b] pyrazine derivatives and pharmaceutical salts thereof that inhibit the expression of transcription factor 1 (HIF-1) gene inducible by hypoxia About.

  Patent specifications WO 04/104002 and WO 04/104003 are pyrido [2,3-b] pyrazines, which are substituted at the 6-position or 7-position with a urea group, a thiourea group, an amidine group or a guanidine group. Said pyrazine may be described. These compounds have the properties of kinases, in particular as inhibitors or modulators of tyrosine kinases and serine / threonine kinases, and have been identified for use as pharmaceuticals. However, the use of these compounds as modulators of lipid kinases alone or in combination with tyrosine kinases and serine / threonine kinases is not described.

  Furthermore, the patent specification WO 99/17759 describes pyrido [2,3-b] pyrazine, especially said pyrazine having an alkyl-substituted, aryl-substituted and heteroaryl-substituted carbamate at the 6-position. . These compounds should be used to modulate serine-threonine protein kinases.

  Patent specification WO 05/007099 describes, among other things, urea substituted pyrido [2,3-b] pyrazine as an inhibitor of serine / threonine kinase PKB. The use in the treatment of said cancer diseases has been described for these compounds. However, specific examples of urea substituted pyridopyrazine having these biological properties are not shown.

  Further examples of pyrido [2,3-b] pyrazine substituted at the 6 and 7 positions with urea are given in the patent specification WO 05/056547. The compounds in said patent specification have been described as inhibitors of protein kinases, in particular GSK-3, Syk and JAK-3. Use in the treatment of said proliferative diseases is indicated among these compounds. The use of these compounds as modulators of lipid kinases alone or in combination with serine / threonine kinases is not described.

  Patent application WO 04/005472 describes, among other things, pyrido [2,3-b] pyrazine substituted at the 6-position with carbamate, said pyridine as an antibacterial substance that suppresses bacterial growth. Antitumor effects are not described.

  Certain diphenylquinoxalines and pyrido [2,3-b] pyrazines having specific alkylpyrrolidine, alkylpiperidine or alkylsulfonamide groups on the phenyl ring, additionally urea substituted at the 6- or 7-position Said compounds which may have a group or carbamate substituent are described in the patent specifications WO 03/084473, WO 03/086394 and WO 03/086403 as inhibitors of the activity of serine / threonine kinase Akt. The use in the treatment of said cancer diseases has been described for these compounds. For the pyrido [2,3-b] pyrazine compounds described therein as examples, no clear indication of biological effects is given.

  Patent specification WO 03/024448 is an amide-substituted and acrylamide-substituted pyrido [2,3-b] pyrazine, which may contain carbamate as an additional substituent and histone for the treatment of cell proliferative disorders Said pyrazines are described which can be used as deacetylase inhibitors.

  Publication (S. Laufer, J. Med. Chem. 2010, 53 (3), 1128-1137) describes pyridinyl pyridopyrazine as a key compound for novel p38α mitogen-activated protein kinase inhibitors doing.

  In another publication (M.R. Dobler, Pest Management Science, 2010, 66 (2), 178-185), pyrido [2,3-b] pyrazine is described as a tubulin polymerization accelerator.

  In the publication (Temple C. et al. 1990), the synthesis of 6-ethylcarbamate substituted pyrido [2,3-b] pyrazine derivatives is described as an example. Antitumor effects are not disclosed or revealed.

  The synthesis of further derivatives of 6-ethylcarbamate substituted pyrido [2,3-b] pyrazine is described in a publication by R. D. Elliott (J. Org. Chem. 1968). The biological effects of these compounds are not described or disclosed.

  A publication by C. Temple (1968) describes the synthesis of 6-ethylcarbamate substituted pyrido [2,3-b] pyrazine and its investigation as a potential antimalarial drug. Antitumor effects are not disclosed or revealed.

  Several PI3K inhibitors (NVP-Bez-235, GDC-0941, XL-147, etc.) are undergoing clinical trials (reviewed by Maira S.M., et al, 2010).

DETAILED DESCRIPTION OF THE INVENTION The subject of the present invention is for the treatment or prevention of physiological and / or pathophysiological conditions mediated by the ras-Raf-Mek-Erk signaling pathway in mammals, in particular humans. It is to provide new compounds that can be used.

［式中、
置換基Ｒ１、Ｒ２、Ｘは、以下の意味を有する：
Ｘは、ＯまたはＳであり、
Ｒ１は、
（Ｉ）非置換のもしくは置換されたアリール、
前記アリール基は、１もしくはそれより多くの同一もしくは異なるＦ、Ｃｌ、Ｂｒ、Ｉ、ＣＦ₃、ＣＮ、ＮＨ₂、ＮＨ−アルキル、ＮＨ−シクロアルキル、ＮＨ−ヘテロシクリル、ＮＨ−アリール、ＮＨ−ヘテロアリール、ＮＨ−アルキル−シクロアルキル、ＮＨ−アルキル−ヘテロシクリル、ＮＨ−アルキル−アリール、ＮＨ−アルキル−ヘテロアリール、ＮＨ−アルキル−ＮＨ₂、ＮＨ−アルキル−ＯＨ、Ｎ（アルキル）₂、ＮＨＣ（Ｏ）−アルキル、ＮＨＣ（Ｏ）−シクロアルキル、ＮＨＣ（Ｏ）−ヘテロシクリル、ＮＨＣ（Ｏ）−アリール、ＮＨＣ（Ｏ）−ヘテロアリール、ＮＨＣ（Ｏ）−アルキル−アリール、ＮＨＣ（Ｏ）−アルキル−ヘテロアリール、ＮＨＳＯ₂−アルキル、ＮＨＳＯ₂−シクロアルキル、ＮＨＳＯ₂−ヘテロシクリル、ＮＨＳＯ₂−アリール、ＮＨＳＯ₂−ヘテロアリール、ＮＨＳＯ₂−アルキル−アリール、ＮＨＳＯ₂−アルキル−ヘテロアリール、ＮＯ₂、ＳＨ、Ｓ−アルキル、Ｓ−アリール、Ｓ−ヘテロアリール、ＯＨ、ＯＣＦ₃、Ｏ−アルキル、Ｏ−シクロアルキル、Ｏ−ヘテロシクリル、Ｏ−アリール、Ｏ−ヘテロアリール、Ｏ−アルキル−シクロアルキル、Ｏ−アルキル−ヘテロシクリル、Ｏ−アルキル−アリール、Ｏ−アルキル−ヘテロアリール、Ｏ−アルキル−ＯＨ、Ｏ−（ＣＨ₂）_n−Ｏ、Ｏ−（−ＣＨ₂−ＣＨ₂−Ｏ−）_n−ＣＨ₂−ＣＨ₂−ＯＨ、ＯＣ（Ｏ）−アルキル、ＯＣ（Ｏ）−シクロアルキル、ＯＣ（Ｏ）−ヘテロシクリル、ＯＣ（Ｏ）−アリール、ＯＣ（Ｏ）−ヘテロアリール、ＯＣ（Ｏ）−アルキル−アリール、ＯＣ（Ｏ）−アルキル−ヘテロアリール、ＯＣ（Ｏ）−ＮＨ−アルキル、ＯＳＯ₃Ｈ、ＯＳＯ₂−アルキル、ＯＳＯ₂−シクロアルキル、ＯＳＯ₂−ヘテロシクリル、ＯＳＯ₂−アリール、ＯＳＯ₂−ヘテロアリール、ＯＳＯ₂−アルキル−アリール、ＯＳＯ₂−アルキル−ヘテロアリール、ＯＰ（Ｏ）（ＯＨ）₂、Ｃ（Ｏ）−アルキル、Ｃ（Ｏ）−アリール、Ｃ（Ｏ）−ヘテロアリール、Ｏ−ＣＯ₂−アルキル、ＣＯ₂Ｈ、ＣＯ₂−アルキル、ＣＯ₂−シクロアルキル、ＣＯ₂−ヘテロシクリル、ＣＯ₂−アリール、ＣＯ₂−ヘテロアリール、ＣＯ₂−アルキル−シクロアルキル、ＣＯ₂−アルキル−ヘテロシクリル、ＣＯ₂−アルキル−アリール、ＣＯ₂−アルキル−ヘテロアリール、Ｃ（Ｏ）−ＮＨ₂、Ｃ（Ｏ）ＮＨ−アルキル、Ｃ（Ｏ）ＮＨ−シクロアルキル、Ｃ（Ｏ）ＮＨ−ヘテロシクリル、Ｃ（Ｏ）ＮＨ−アリール、Ｃ（Ｏ）ＮＨ−ヘテロアリール、Ｃ（Ｏ）ＮＨ−アルキル−シクロアルキル、Ｃ（Ｏ）ＮＨ−アルキル−ヘテロシクリル、Ｃ（Ｏ）ＮＨ−アルキル−アリール、Ｃ（Ｏ）ＮＨ−アルキル−ヘテロアリール、Ｃ（Ｏ）Ｎ（アルキル）₂、Ｃ（Ｏ）Ｎ（シクロアルキル）₂、Ｃ（Ｏ）Ｎ（アリール）₂、Ｃ（Ｏ）Ｎ（ヘテロアリール）₂、ＳＯ−アルキル、ＳＯ−アリール、ＳＯ₂−アルキル、ＳＯ₂−ヘテロシクリル、ＳＯ₂アリール、ＳＯ₂ＮＨ₂、ＳＯ₂ＮＨ−アルキル、ＳＯ₂ＮＨ−アリール、ＳＯ₂ＮＨ−ヘテロアリール、ＳＯ₂ＮＨ−アルキル−アリール、ＳＯ₃Ｈ、ＳＯ₂Ｏ−アルキル、ＳＯ₂Ｏ−アリール、ＳＯ₂Ｏ−アルキル−アリール、アルキル、シクロアルキル、ヘテロシクリル、アリールまたはヘテロアリールで置換されていてよく、ｎは、０、１、２または３の値を有してよく、かつそれらの部分に関する前記のアルキル置換基、シクロアルキル置換基、ヘテロシクリル置換基、アリール置換基、ヘテロアリール置換基、アルキル−シクロアルキル置換基、アルキル−ヘテロシクリル置換基、アルキル−アリール置換基およびアルキル−ヘテロアリール置換基もさらに置換されていてよく、
（ＩＩ）非置換のもしくは置換されたヘテロアリール、
前記ヘテロアリール基は、１もしくはそれより多くの同一もしくは異なるＦ、Ｃｌ、Ｂｒ、Ｉ、ＣＦ₃、ＣＮ、ＮＨ₂、ＮＨ−アルキル、ＮＨ−シクロアルキル、ＮＨ−ヘテロシクリル、ＮＨ−アリール、ＮＨ−ヘテロアリール、ＮＨ−アルキル−シクロアルキル、ＮＨ−アルキル−ヘテロシクリル、ＮＨ−アルキル−アリール、ＮＨ−アルキル−ヘテロアリール、ＮＨ−アルキル−ＮＨ₂、ＮＨ−アルキル−ＯＨ、Ｎ（アルキル）₂、ＮＨＣ（Ｏ）−アルキル、ＮＨＣ（Ｏ）−シクロアルキル、ＮＨＣ（Ｏ）−ヘテロシクリル、ＮＨＣ（Ｏ）−アリール、ＮＨＣ（Ｏ）−ヘテロアリール、ＮＨＣ（Ｏ）−アルキル−アリール、ＮＨＣ（Ｏ）−アルキル−ヘテロアリール、ＮＨＳＯ₂−アルキル、ＮＨＳＯ₂−シクロアルキル、ＮＨＳＯ₂−ヘテロシクリル、ＮＨＳＯ₂−アリール、ＮＨＳＯ₂−ヘテロアリール、ＮＨＳＯ₂−アルキル−アリール、ＮＨＳＯ₂−アルキル−ヘテロアリール、ＮＯ₂、ＳＨ、Ｓ−アルキル、Ｓ−アリール、Ｓ−ヘテロアリール、ＯＨ、ＯＣＦ₃、Ｏ−アルキル、Ｏ−シクロアルキル、Ｏ−アリール、Ｏ−ヘテロアリール、Ｏ−アルキル−シクロアルキル、Ｏ−アルキル−ヘテロシクリル、Ｏ−アルキル−アリール、Ｏ−アルキル−ヘテロアリール、ＯＣ（Ｏ）−アルキル、ＯＣ（Ｏ）−シクロアルキル、ＯＣ（Ｏ）−ヘテロシクリル、ＯＣ（Ｏ）−アリール、ＯＣ（Ｏ）−ヘテロアリール、ＯＣ（Ｏ）−アルキル−アリール、ＯＣ（Ｏ）−アルキル−ヘテロアリール、ＯＳＯ₃Ｈ、ＯＳＯ₂−アルキル、ＯＳＯ₂−シクロアルキル、ＯＳＯ₂−ヘテロシクリル、ＯＳＯ₂−アリール、ＯＳＯ₂−ヘテロアリール、ＯＳＯ₂−アルキル−アリール、ＯＳＯ₂−アルキル−ヘテロアリール、ＯＰ（Ｏ）（ＯＨ）₂、Ｃ（Ｏ）−アルキル、Ｃ（Ｏ）−アリール、Ｃ（Ｏ）−ヘテロアリール、ＣＯ₂Ｈ、ＣＯ₂−アルキル、ＣＯ₂−シクロアルキル、ＣＯ₂−ヘテロシクリル、ＣＯ₂−アリール、ＣＯ₂−ヘテロアリール、ＣＯ₂−アルキル−シクロアルキル、ＣＯ₂−アルキル−ヘテロシクリル、ＣＯ₂−アルキル−アリール、ＣＯ₂−アルキル−ヘテロアリール、Ｃ（Ｏ）−ＮＨ₂、Ｃ（Ｏ）ＮＨ−アルキル、Ｃ（Ｏ）ＮＨ−シクロアルキル、Ｃ（Ｏ）ＮＨ−ヘテロシクリル、Ｃ（Ｏ）ＮＨ−アリール、Ｃ（Ｏ）ＮＨ−ヘテロアリール、Ｃ（Ｏ）ＮＨ−アルキル−シクロアルキル、Ｃ（Ｏ）ＮＨ−アルキル−ヘテロシクリル、Ｃ（Ｏ）ＮＨ−アルキル−アリール、Ｃ（Ｏ）ＮＨ−アルキル−ヘテロアリール、Ｃ（Ｏ）Ｎ（アルキル）₂、Ｃ（Ｏ）Ｎ（シクロアルキル）₂、Ｃ（Ｏ）Ｎ（アリール）₂、Ｃ（Ｏ）Ｎ（ヘテロアリール）₂、ＳＯ₂ＮＨ₂、ＳＯ₂ＮＨ−アルキル、ＳＯ₂ＮＨ−アリール、ＳＯ₂ＮＨ−ヘテロアリール、ＳＯ₂ＮＨ−アルキル−アリール、ＳＯ₃Ｈ、ＳＯ₂Ｏ−アルキル、ＳＯ₂Ｏ−アリール、ＳＯ₂Ｏ−アルキル−アリール、アルキル、シクロアルキル、ヘテロシクリル、アルキル−シクロアルキル、アルキル−ヘテロシクリル、アルキル−アリール、アルキル−ヘテロアリール、アリールまたはヘテロアリールで置換されていてよく、かつそれらの部分に関する前記のアルキル置換基、シクロアルキル置換基、ヘテロシクリル置換基、アルキル−シクロアルキル置換基、アルキル−ヘテロシクリル置換基、アルキル−アリール置換基、アルキル−ヘテロアリール置換基、アリール置換基およびヘテロアリール置換基もさらに置換されていてよく、
（ＩＩＩ）ＮＲ３Ｒ４、
Ｒ３およびＲ４は、互いに独立して、水素、アルキル、シクロアルキル、ヘテロシクリル、アリール、ヘテロアリール、アルキル−シクロアルキル、アルキル−ヘテロシクリル、アルキル−アリールまたはアルキル−ヘテロアリールであってよく、かつそれらの部分に関する前記のアルキル置換基、シクロアルキル置換基、ヘテロシクリル置換基、アリール置換基およびヘテロアリール置換基、アルキル−シクロアルキル置換基、アルキル−ヘテロシクリル置換基、アルキル−アリール置換基またはアルキル−ヘテロアリール置換基もさらに置換されていてよく、または
Ｒ３およびＲ４は、一緒になって、シクロアルキルまたはヘテロシクリルを意味し、その際、それらの部分に関するシクロアルキルおよびヘテロシクリルもさらに置換されていてよく、
であり、かつ
Ｒ２は、
（Ｉ）非置換のもしくは置換されたアルキル−アリール、
前記アルキル−アリール基は、１もしくはそれより多くの同一もしくは異なるＦ、Ｃｌ、Ｂｒ、Ｉ、ＣＦ₃、ＣＮ、ＮＨ₂、ＮＨ−アルキル、ＮＨ−シクロアルキル、ＮＨ−ヘテロシクリル、ＮＨ−アリール、ＮＨ−ヘテロアリール、ＮＨ−アルキル−シクロアルキル、ＮＨ−アルキル−ヘテロシクリル、ＮＨ−アルキル−アリール、ＮＨ−アルキル−ヘテロアリール、Ｎ（アルキル）₂、ＮＨＣ（Ｏ）−アルキル、ＮＨＣ（Ｏ）−シクロアルキル、ＮＨＣ（Ｏ）−ヘテロシクリル、ＮＨＣ（Ｏ）−アリール、ＮＨＣ（Ｏ）−ヘテロアリール、ＮＨＣ（Ｏ）−アルキル−アリール、ＮＨＣ（Ｏ）−アルキル−ヘテロアリール、ＮＨＳＯ₂−アルキル、ＮＨＳＯ₂−シクロアルキル、ＮＨＳＯ₂−ヘテロシクリル、ＮＨＳＯ₂−アリール、ＮＨＳＯ₂−ヘテロアリール、ＮＨＳＯ₂−アルキル−アリール、ＮＨＳＯ₂−アルキル−ヘテロアリール、ＮＯ₂、ＳＨ、Ｓ−アルキル、Ｓ−シクロアルキル、Ｓ−ヘテロシクリル、Ｓ−アリール、Ｓ−ヘテロアリール、＝Ｏ、ＯＨ、ＯＣＦ₃、Ｏ−アルキル、Ｏ−シクロアルキル、Ｏ−ヘテロシクリル、Ｏ−アリール、Ｏ−ヘテロアリール、Ｏ−アルキル−シクロアルキル、Ｏ−アルキル−ヘテロシクリル、Ｏ−アルキル−アリール、Ｏ−アルキル−ヘテロアリール、ＯＣ（Ｏ）−アルキル、ＯＣ（Ｏ）−シクロアルキル、ＯＣ（Ｏ）−ヘテロシクリル、ＯＣ（Ｏ）−アリール、ＯＣ（Ｏ）−ヘテロアリール、ＯＣ（Ｏ）−アルキル−アリール、ＯＣ（Ｏ）−アルキル−ヘテロアリール、ＯＳＯ₃Ｈ、ＯＳＯ₂−アルキル、ＯＳＯ₂−シクロアルキル、ＯＳＯ₂−ヘテロシクリル、ＯＳＯ₂−アリール、ＯＳＯ₂−ヘテロアリール、ＯＳＯ₂−アルキル−アリール、ＯＳＯ₂−アルキル−ヘテロアリール、ＯＰ（Ｏ）（ＯＨ）₂、Ｃ（Ｏ）−アルキル、Ｃ（Ｏ）−アリール、Ｃ（Ｏ）−ヘテロアリール、ＣＯ₂Ｈ、ＣＯ₂−アルキル、ＣＯ₂−シクロアルキル、ＣＯ₂−ヘテロシクリル、ＣＯ₂−アリール、ＣＯ₂−ヘテロアリール、ＣＯ₂−アルキル−シクロアルキル、ＣＯ₂−アルキル−ヘテロシクリル、ＣＯ₂−アルキル−アリール、ＣＯ₂−アルキル−ヘテロアリール、Ｃ（Ｏ）−ＮＨ₂、Ｃ（Ｏ）ＮＨ−アルキル、Ｃ（Ｏ）ＮＨ−シクロアルキル、Ｃ（Ｏ）ＮＨ−ヘテロシクリル、Ｃ（Ｏ）ＮＨ−アリール、Ｃ（Ｏ）ＮＨ−ヘテロアリール、Ｃ（Ｏ）ＮＨ−アルキル−シクロアルキル、Ｃ（Ｏ）ＮＨ−アルキル−ヘテロシクリル、Ｃ（Ｏ）ＮＨ−アルキル−アリール、Ｃ（Ｏ）ＮＨ−アルキル−ヘテロアリール、Ｃ（Ｏ）Ｎ（アルキル）₂、Ｃ（Ｏ）Ｎ（シクロアルキル）₂、Ｃ（Ｏ）Ｎ（アリール）₂、Ｃ（Ｏ）Ｎ（ヘテロアリール）₂、ＳＯ−アルキル、ＳＯ−アリール、ＳＯ₂−アルキル、ＳＯ₂−アリール、ＳＯ₂ＮＨ₂、ＳＯ₂ＮＨ−アルキル、ＳＯ₂ＮＨ−アリール、ＳＯ₂ＮＨ−ヘテロアリール、ＳＯ₂ＮＨ−アルキル−アリール、ＳＯ₃Ｈ、ＳＯ₂Ｏ−アルキル、ＳＯ₂Ｏ−アリール、ＳＯ₂Ｏ−アルキル−アリール、アルキル、シクロアルキル、ヘテロシクリル、アリールまたはヘテロアリールで置換されていてよく、
（ＩＩ）非置換のもしくは置換されたアルキル−ヘテロアリール、
前記アルキル−ヘテロアリール基は、１もしくはそれより多くの同一もしくは異なるＦ、Ｃｌ、Ｂｒ、Ｉ、ＣＦ₃、ＣＮ、ＮＨ₂、ＮＨ−アルキル、ＮＨ−シクロアルキル、ＮＨ−ヘテロシクリル、ＮＨ−アリール、ＮＨ−ヘテロアリール、ＮＨ−アルキル−シクロアルキル、ＮＨ−アルキル−ヘテロシクリル、ＮＨ−アルキル−アリール、ＮＨ−アルキル−ヘテロアリール、Ｎ（アルキル）₂、ＮＨＣ（Ｏ）−アルキル、ＮＨＣ（Ｏ）−シクロアルキル、ＮＨＣ（Ｏ）−ヘテロシクリル、ＮＨＣ（Ｏ）−アリール、ＮＨＣ（Ｏ）−ヘテロアリール、ＮＨＣ（Ｏ）−アルキル−アリール、ＮＨＣ（Ｏ）−アルキル−ヘテロアリール、ＮＨＳＯ₂−アルキル、ＮＨＳＯ₂−シクロアルキル、ＮＨＳＯ₂−ヘテロシクリル、ＮＨＳＯ₂−アリール、ＮＨＳＯ₂−ヘテロアリール、ＮＨＳＯ₂−アルキル−アリール、ＮＨＳＯ₂−アルキル−ヘテロアリール、ＮＯ₂、ＳＨ、Ｓ−アルキル、Ｓ−シクロアルキル、Ｓ−ヘテロシクリル、Ｓ−アリール、Ｓ−ヘテロアリール、ＯＨ、ＯＣＦ₃、Ｏ−アルキル、Ｏ−シクロアルキル、Ｏ−ヘテロシクリル、Ｏ−アリール、Ｏ−ヘテロアリール、Ｏ−アルキル−シクロアルキル、Ｏ−アルキル−ヘテロシクリル、Ｏ−アルキル−アリール、Ｏ−アルキル−ヘテロアリール、ＯＣ（Ｏ）−アルキル、ＯＣ（Ｏ）−シクロアルキル、ＯＣ（Ｏ）−ヘテロシクリル、ＯＣ（Ｏ）−アリール、ＯＣ（Ｏ）−ヘテロアリール、ＯＣ（Ｏ）−アルキル−アリール、ＯＣ（Ｏ）−アルキル−ヘテロアリール、ＯＳＯ₃Ｈ、ＯＳＯ₂−アルキル、ＯＳＯ₂−シクロアルキル、ＯＳＯ₂−ヘテロシクリル、ＯＳＯ₂−アリール、ＯＳＯ₂−ヘテロアリール、ＯＳＯ₂−アルキル−アリール、ＯＳＯ₂−アルキル−ヘテロアリール、ＯＰ（Ｏ）（ＯＨ）₂、Ｃ（Ｏ）−アルキル、Ｃ（Ｏ）−アリール、Ｃ（Ｏ）−ヘテロアリール、ＣＯ₂Ｈ、ＣＯ₂−アルキル、ＣＯ₂−シクロアルキル、ＣＯ₂−ヘテロシクリル、ＣＯ₂−アリール、ＣＯ₂−ヘテロアリール、ＣＯ₂−アルキル−シクロアルキル、ＣＯ₂−アルキル−ヘテロシクリル、ＣＯ₂−アルキル−アリール、ＣＯ₂−アルキル−ヘテロアリール、Ｃ（Ｏ）−ＮＨ₂、Ｃ（Ｏ）ＮＨ−アルキル、Ｃ（Ｏ）ＮＨ−シクロアルキル、Ｃ（Ｏ）ＮＨ−ヘテロシクリル、Ｃ（Ｏ）ＮＨ−アリール、Ｃ（Ｏ）ＮＨ−ヘテロアリール、Ｃ（Ｏ）ＮＨ−アルキル−シクロアルキル、Ｃ（Ｏ）ＮＨ−アルキル−ヘテロシクリル、Ｃ（Ｏ）ＮＨ−アルキル−アリール、Ｃ（Ｏ）ＮＨ−アルキル−ヘテロアリール、Ｃ（Ｏ）Ｎ（アルキル）₂、Ｃ（Ｏ）Ｎ（シクロアルキル）₂、Ｃ（Ｏ）Ｎ（アリール）₂、Ｃ（Ｏ）Ｎ（ヘテロアリール）₂、ＳＯ−アルキル、ＳＯ−アリール、ＳＯ₂−アルキル、ＳＯ₂−アリール、ＳＯ₂ＮＨ₂、ＳＯ₂ＮＨ−アルキル、ＳＯ₂ＮＨ−アリール、ＳＯ₂ＮＨ−ヘテロアリール、ＳＯ₂ＮＨ−アルキル−アリール、ＳＯ₃Ｈ、ＳＯ₂Ｏ−アルキル、ＳＯ₂Ｏ−アリール、ＳＯ₂Ｏ−アルキル−アリール、シクロアルキル、ヘテロシクリル、アリールまたはヘテロアリールで置換されていてよく、
である］による化合物、その生理学的に認容性の塩の、それらのラセミ体の形、その純粋なエナンチオマーおよび／またはジアステレオマーの形、またはこれらのエナンチオマーおよび／またはジアステレオマーの混合物の形、またはそれらの互変異性体の形であって、哺乳動物における、ras-Raf-Mek-Erkシグナル伝達経路によって媒介される、生理学的および／または病態生理学的な状態の治療または予防のための医薬品の製造のために使用できるものの製造によって解決された。 The above object of the present invention surprisingly, in one aspect, is the general formula (I)

[Where:
The substituents R1, R2, X have the following meanings:
X is O or S;
R1 is
(I) unsubstituted or substituted aryl,
The aryl group, one or more identical or different F, Cl, Br, I, CF 3, CN, NH 2, NH- alkyl, NH- cycloalkyl, NH- heterocyclyl, NH- aryl, NH- heteroaryl aryl, NH- alkyl - cycloalkyl, NH- alkyl - heterocyclyl, NH- alkyl - aryl, NH- alkyl - heteroaryl, NH- alkyl -NH _2, NH- alkyl -OH, N (alkyl) _2, NHC (O ) -Alkyl, NHC (O) -cycloalkyl, NHC (O) -heterocyclyl, NHC (O) -aryl, NHC (O) -heteroaryl, NHC (O) -alkyl-aryl, NHC (O) -alkyl- heteroaryl, NHSO ₂ - alkyl, NHSO ₂ - cycloalkyl, NHSO ₂ - heteroaryl Krill, NHSO ₂ - aryl, NHSO ₂ - heteroaryl, NHSO ₂ - alkyl - aryl, NHSO ₂ - alkyl - heteroaryl, NO _2, SH, S- alkyl, S- aryl, S- heteroaryl, OH, OCF ₃ O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl, O-alkyl-heteroaryl, O - alkyl _{-OH, O- (CH 2) n} -O, O - (- CH 2 -CH 2 -O-) n -CH 2 -CH 2 -OH, OC (O) - alkyl, OC (O) - Cycloalkyl, OC (O) -heterocyclyl, OC (O) -aryl, OC (O) -heteroaryl, OC (O) -alkyl-aryl OC (O) - alkyl - heteroaryl, OC (O) -NH- alkyl, OSO ₃ H, OSO ₂ - alkyl, OSO ₂ - cycloalkyl, OSO ₂ - heterocyclyl, OSO ₂ - aryl, OSO ₂ - heteroaryl, OSO ₂ - alkyl - aryl, OSO ₂ - alkyl - heteroaryl, OP (O) (OH) 2, C (O) - alkyl, C (O) - aryl, C (O) - heteroaryl, O-CO ₂ - alkyl, CO ₂ H, CO ₂ - alkyl, CO ₂ - cycloalkyl, CO ₂ - heterocyclyl, CO ₂ - aryl, CO ₂ - heteroaryl, CO ₂ - alkyl - cycloalkyl, CO ₂ - alkyl - heterocyclyl, CO ₂ - alkyl - aryl, CO ₂ - alkyl - _{heteroaryl, C (O) -NH 2,} C (O) NH- alkyl, C ( O) NH-cycloalkyl, C (O) NH-heterocyclyl, C (O) NH-aryl, C (O) NH-heteroaryl, C (O) NH-alkyl-cycloalkyl, C (O) NH-alkyl -Heterocyclyl, C (O) NH-alkyl-aryl, C (O) NH-alkyl-heteroaryl, C (O) N (alkyl) ₂ , C (O) N (cycloalkyl) ₂ , C (O) N (Aryl) ₂ , C (O) N (heteroaryl) ₂ , SO-alkyl, SO-aryl, SO ₂ -alkyl, SO ₂ -heterocyclyl, SO ₂ aryl, SO ₂ NH ₂ , SO ₂ NH-alkyl, SO ₂ NH- aryl, SO ₂ NH- heteroaryl, SO ₂ NH- alkyl - aryl, SO ₃ H, SO ₂ O- alkyl, SO ₂ O-aryl, SO ₂ O-alkyl - aryl May be substituted with alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, n may have a value of 0, 1, 2 or 3, and the alkyl substituents as defined above for those moieties, cycloalkyl substitution Groups, heterocyclyl substituents, aryl substituents, heteroaryl substituents, alkyl-cycloalkyl substituents, alkyl-heterocyclyl substituents, alkyl-aryl substituents and alkyl-heteroaryl substituents may be further substituted,
(II) unsubstituted or substituted heteroaryl,
It said heteroaryl group is 1 or more identical or different F, Cl, Br, I, CF 3, CN, NH 2, NH- alkyl, NH- cycloalkyl, NH- heterocyclyl, NH- aryl, NH- heteroaryl, NH- alkyl - cycloalkyl, NH- alkyl - heterocyclyl, NH- alkyl - aryl, NH- alkyl - heteroaryl, NH- alkyl -NH _2, NH- alkyl -OH, N (alkyl) _2, NHC ( O) -alkyl, NHC (O) -cycloalkyl, NHC (O) -heterocyclyl, NHC (O) -aryl, NHC (O) -heteroaryl, NHC (O) -alkyl-aryl, NHC (O) -alkyl - heteroaryl, NHSO ₂ - alkyl, NHSO ₂ - cycloalkyl, NHSO ₂ - Heterocyclyl, NHSO ₂ - aryl, NHSO ₂ - heteroaryl, NHSO ₂ - alkyl - aryl, NHSO ₂ - alkyl - heteroaryl, NO _2, SH, S- alkyl, S- aryl, S- heteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl, O-alkyl-heteroaryl, OC (O)- Alkyl, OC (O) -cycloalkyl, OC (O) -heterocyclyl, OC (O) -aryl, OC (O) -heteroaryl, OC (O) -alkyl-aryl, OC (O) -alkyl-heteroaryl , OSO ₃ H, OSO ₂ - alkyl, OSO ₂ - cycloalkyl, OSO ₂ - Haitai Cyclyl, OSO ₂ - aryl, OSO ₂ - heteroaryl, OSO ₂ - alkyl - aryl, OSO ₂ - alkyl - heteroaryl, OP (O) (OH) 2, C (O) - alkyl, C (O) - aryl , C (O) - heteroaryl, CO ₂ H, CO ₂ - alkyl, CO ₂ - cycloalkyl, CO ₂ - heterocyclyl, CO ₂ - aryl, CO ₂ - heteroaryl, CO ₂ - alkyl - cycloalkyl, CO ₂ - alkyl - heterocyclyl, CO ₂ - alkyl - aryl, CO ₂ - alkyl - _{heteroaryl, C (O) -NH 2,} C (O) NH- alkyl, C (O) NH- cycloalkyl, C (O) NH -Heterocyclyl, C (O) NH-aryl, C (O) NH-heteroaryl, C (O) NH-alkyl-cycloalkyl, C (O) NH -Alkyl-heterocyclyl, C (O) NH-alkyl-aryl, C (O) NH-alkyl-heteroaryl, C (O) N (alkyl) ₂ , C (O) N (cycloalkyl) ₂ , C (O ) N (aryl) _2, C (O) N _{(heteroaryl) 2, SO 2 NH 2,} SO 2 NH- alkyl, SO ₂ NH- aryl, SO ₂ NH- heteroaryl, SO ₂ NH- alkyl - aryl, SO ₃ H, SO ₂ O- alkyl, SO ₂ O-aryl, SO ₂ O-alkyl - aryl, alkyl, cycloalkyl, heterocyclyl, alkyl - cycloalkyl, alkyl - heterocyclyl, alkyl - aryl, alkyl - heteroaryl, aryl Or the above-mentioned alkyl substituents, cycloalkyl, which may be substituted with heteroaryl, and relating to those moieties Substituent, heterocyclyl substituents include alkyl - cycloalkyl substituents include alkyl - heterocyclyl substituents include alkyl - aryl substituent, an alkyl - heteroaryl substituent, an aryl substituent and heteroaryl substituents may be further substituted,
(III) NR3R4,
R3 and R4 may be, independently of one another, hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkyl-cycloalkyl, alkyl-heterocyclyl, alkyl-aryl or alkyl-heteroaryl, and moieties thereof Alkyl substituents, cycloalkyl substituents, heterocyclyl substituents, aryl substituents and heteroaryl substituents, alkyl-cycloalkyl substituents, alkyl-heterocyclyl substituents, alkyl-aryl substituents or alkyl-heteroaryl substituents Can be further substituted, or R3 and R4 taken together mean cycloalkyl or heterocyclyl, wherein cycloalkyl and heterocyclyl for those moieties are also further substituted. Well it is,
And R2 is
(I) unsubstituted or substituted alkyl-aryl,
The alkyl - aryl groups, one or more identical or different F, Cl, Br, I, CF 3, CN, NH 2, NH- alkyl, NH- cycloalkyl, NH- heterocyclyl, NH- aryl, NH -Heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, N (alkyl) ₂ , NHC (O) -alkyl, NHC (O) -cycloalkyl , NHC (O) -heterocyclyl, NHC (O) -aryl, NHC (O) -heteroaryl, NHC (O) -alkyl-aryl, NHC (O) -alkyl-heteroaryl, NHSO ₂ -alkyl, NHSO ₂ — cycloalkyl, NHSO ₂ - heterocyclyl, NHSO ₂ - aryl, NH O ₂ - heteroaryl, NHSO ₂ - alkyl - aryl, NHSO ₂ - alkyl - heteroaryl, NO _2, SH, S- alkyl, S- cycloalkyl, S- heterocyclyl, S- aryl, S- heteroaryl, = O , OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl, O-alkyl -Heteroaryl, OC (O) -alkyl, OC (O) -cycloalkyl, OC (O) -heterocyclyl, OC (O) -aryl, OC (O) -heteroaryl, OC (O) -alkyl-aryl, OC (O) - alkyl - heteroaryl, OSO ₃ H, OSO ₂ - alkyl, OSO ₂ - cyclo Alkyl, OSO ₂ - heterocyclyl, OSO ₂ - aryl, OSO ₂ - heteroaryl, OSO ₂ - alkyl - aryl, OSO ₂ - alkyl - heteroaryl, OP (O) (OH) 2, C (O) - alkyl, C (O) - aryl, C (O) - heteroaryl, CO ₂ H, CO ₂ - alkyl, CO ₂ - cycloalkyl, CO ₂ - heterocyclyl, CO ₂ - aryl, CO ₂ - heteroaryl, CO ₂ - alkyl - cycloalkyl, CO ₂ - alkyl - heterocyclyl, CO ₂ - alkyl - aryl, CO ₂ - alkyl - _{heteroaryl, C (O) -NH 2,} C (O) NH- alkyl, C (O) NH- cycloalkyl, C (O) NH-heterocyclyl, C (O) NH-aryl, C (O) NH-heteroaryl, C (O) NH-alkyl-cycl Roalkyl, C (O) NH-alkyl-heterocyclyl, C (O) NH-alkyl-aryl, C (O) NH-alkyl-heteroaryl, C (O) N (alkyl) ₂ , C (O) N (cyclo _{alkyl) 2, C (O) N} ( _{aryl) 2, C (O) N} ( heteroaryl) _2, SO- alkyl, SO- aryl, SO ₂ - alkyl, SO ₂ - aryl, SO ₂ NH _2, SO ₂ NH- alkyl, SO ₂ NH- aryl, SO ₂ NH- heteroaryl, SO ₂ NH- alkyl - aryl, SO ₃ H, SO ₂ O- alkyl, SO ₂ O-aryl, SO ₂ O-alkyl - aryl, alkyl , Substituted with cycloalkyl, heterocyclyl, aryl or heteroaryl,
(II) unsubstituted or substituted alkyl-heteroaryl,
The alkyl - heteroaryl group, one or more identical or different F, Cl, Br, I, CF 3, CN, NH 2, NH- alkyl, NH- cycloalkyl, NH- heterocyclyl, NH- aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, N (alkyl) ₂ , NHC (O) -alkyl, NHC (O) -cyclo Alkyl, NHC (O) -heterocyclyl, NHC (O) -aryl, NHC (O) -heteroaryl, NHC (O) -alkyl-aryl, NHC (O) -alkyl-heteroaryl, NHSO ₂ -alkyl, NHSO ₂ - cycloalkyl, NHSO ₂ - heterocyclyl, NHSO ₂ - aryl NHSO ₂ - heteroaryl, NHSO ₂ - alkyl - aryl, NHSO ₂ - alkyl - heteroaryl, NO _2, SH, S- alkyl, S- cycloalkyl, S- heterocyclyl, S- aryl, S- heteroaryl, OH, OCF _3, O- alkyl, O- cycloalkyl, O- heterocyclyl, O- aryl, O- heteroaryl, O- alkyl - cycloalkyl, O- alkyl - heterocyclyl, O- alkyl - aryl, O- alkyl - heteroaryl OC (O) -alkyl, OC (O) -cycloalkyl, OC (O) -heterocyclyl, OC (O) -aryl, OC (O) -heteroaryl, OC (O) -alkyl-aryl, OC (O ) - alkyl - heteroaryl, OSO ₃ H, OSO ₂ - alkyl, OSO ₂ - cyclo Alkyl, OSO ₂ - heterocyclyl, OSO ₂ - aryl, OSO ₂ - heteroaryl, OSO ₂ - alkyl - aryl, OSO ₂ - alkyl - heteroaryl, OP (O) (OH) 2, C (O) - alkyl, C (O) - aryl, C (O) - heteroaryl, CO ₂ H, CO ₂ - alkyl, CO ₂ - cycloalkyl, CO ₂ - heterocyclyl, CO ₂ - aryl, CO ₂ - heteroaryl, CO ₂ - alkyl - cycloalkyl, CO ₂ - alkyl - heterocyclyl, CO ₂ - alkyl - aryl, CO ₂ - alkyl - _{heteroaryl, C (O) -NH 2,} C (O) NH- alkyl, C (O) NH- cycloalkyl, C (O) NH-heterocyclyl, C (O) NH-aryl, C (O) NH-heteroaryl, C (O) NH-alkyl-cycl Roalkyl, C (O) NH-alkyl-heterocyclyl, C (O) NH-alkyl-aryl, C (O) NH-alkyl-heteroaryl, C (O) N (alkyl) ₂ , C (O) N (cyclo _{alkyl) 2, C (O) N} ( _{aryl) 2, C (O) N} ( heteroaryl) _2, SO- alkyl, SO- aryl, SO ₂ - alkyl, SO ₂ - aryl, SO ₂ NH _2, SO ₂ NH- alkyl, SO ₂ NH- aryl, SO ₂ NH- heteroaryl, SO ₂ NH- alkyl - aryl, SO ₃ H, SO ₂ O- alkyl, SO ₂ O-aryl, SO ₂ O-alkyl - aryl, cycloalkyl May be substituted with alkyl, heterocyclyl, aryl or heteroaryl;
In the form of their racemic forms, their racemic forms, their pure enantiomers and / or diastereomers, or the mixtures of these enantiomers and / or diastereomers. Or in the form of tautomers thereof, for the treatment or prevention of physiological and / or pathophysiological conditions mediated by the ras-Raf-Mek-Erk signaling pathway in mammals Solved by the manufacture of what can be used for the manufacture of pharmaceuticals.

In one preferred embodiment, the alkyl group is represented by the general formula (I), and the alkyl group is “methyl, ethyl, n-propyl, 2-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, isopentyl. , neopentyl, n- hexyl, 2-hexyl, n- octyl, Echirueniru (vinyl), ethynyl, propenyl _{(-CH 2 CH = CH 2;} -CH = CH-CH 3, -C (= CH 2) -CH 3 ), Propynyl (—CH ₂ —C≡CH, —C≡C—CH ₃ ), butenyl, butynyl, pentenyl, pentynyl, hexenyl, hexynyl, heptenyl, heptynyl, octenyl, octynyl ” A signal selected from the group consisting of the PI3K-Akt signaling pathway and / or the ras-Raf-Mek-Erk signaling pathway in a mammal Said compound is prepared which can be used for the manufacture of a medicament for the treatment or prevention of physiological and / or pathophysiological conditions mediated by a transmission pathway.

  In a further preferred embodiment, the compound of the general formula (I) in which the heterocyclyl group is selected from the group consisting of “tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl” Manufactured for use.

  In a further preferred embodiment, the heteroaryl group of the general formula (I) is selected from the group “pyrrolyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, phthalazinyl, A compound selected from the group consisting of indolyl, indazolyl, indolizinyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl, acridinyl is prepared for the aforementioned use.

In one preferred embodiment, the alkyl group is represented by the general formula (I), and the alkyl group is “methyl, ethyl, n-propyl, 2-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, isopentyl. , neopentyl, n- hexyl, 2-hexyl, n- octyl, Echirueniru (vinyl), ethynyl, propenyl _{(-CH 2 CH = CH 2;} -CH = CH-CH 3, -C (= CH 2) -CH 3 ), Propynyl (—CH ₂ —C≡CH, —C≡C—CH ₃ ), butenyl, butynyl, pentenyl, pentynyl, hexenyl, hexynyl, heptenyl, heptynyl, octenyl, octynyl ”and / or Or a heterocyclyl group such as "tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholini A heteroaryl group selected from the group consisting of: pyrrolyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, phthalazinyl, indolyl, indazolyl, indolizinyl, benzimidazolyl A compound selected from the group consisting of quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl, acridinyl "is prepared for the aforementioned use.

The above object of the invention is surprisingly, in a further aspect, in the following compounds:
Compound 90:
1- [3- (4- {2- [2- (2-hydroxy-ethoxy) -ethoxy] -ethoxy} -phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4 -Phenyl-butyl) -urea

Compound 91:
1- [3- (3,5-Dimethyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 92:
1- (4-Phenyl-butyl) -3- [3- (2,3,4-trimethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -urea

Compound 93:
1- [3- (4-Methyl-piperazin-1-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 94:
1- [3- (3H-Benzimidazol-5-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 95:
1- [3- (3-Amino-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 96:
1- (4-Phenyl-butyl) -3- (3-piperazin-1-yl-pyrido [2,3-b] pyrazin-6-yl) -urea; hydrochloride

Compound 97:
1- [3- (1-Methyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-p-tolyl-butyl) -urea

Compound 98:
1- [3- (3,4-Dimethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea

Compound 99:
1- [4- (4-Fluoro-phenyl) -butyl] -3- [3- (1-methyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl]- urea

Compound 100:
1- (4-Methyl-4-phenyl-pentyl) -3- [3- (1-propyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -urea

Compound 101:
1- [3- (2,4-Dimethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 102:
1- [3- (2-Ethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 103:
1- [3- (3,5-Dichloro-4-hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 104:
1- [3- (3-Hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 105:
1- (4-Phenyl-butyl) -3- [3- (2H-pyrazol-3-yl) -pyrido [2,3-b] pyrazin-6-yl] -urea

Compound 106:
1- [3- (4-Hydroxy-2-methyl-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 107:
Acetic acid 4- {6- [3- (4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -phenyl ester

Compound 108:
1- [3- (1-Ethyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 109:
1- [3- (3-Bromo-4-hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 110:
1- (4-Phenyl-butyl) -3- (3-pyridin-3-yl-pyrido [2,3-b] pyrazin-6-yl) -urea

Compound 111:
1- [3- (1-Methyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (1,2,3,4-tetrahydro-naphthalene-2 -Ylmethyl) -urea

Compound 112:
1- [3- (2,3-Dimethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea

Compound 113:
1- [3- (5-Methyl-1-phenyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 114:
1- [3- (1-Butyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 115:
1- [4- (4-Methoxy-phenyl) -butyl] -3- [3- (1-methyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl]- urea

Compound 116:
1- (4-Phenyl-butyl) -3- [3- (piperidin-4-ylamino) -pyrido [2,3-b] pyrazin-6-yl] -urea

Compound 117:
1- (4-Phenyl-butyl) -3- {3-[(pyridin-4-ylmethyl) -amino] -pyrido [2,3-b] pyrazin-6-yl} -urea

Compound 118:
1- [3- (4-Methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 119:
1- (4-Phenyl-butyl) -3- (3-propylamino-pyrido [2,3-b] pyrazin-6-yl) -urea

Compound 120:
1- (4-Phenyl-butyl) -3- (3-o-tolyl-pyrido [2,3-b] pyrazin-6-yl) -urea

Compound 121:
3- {6- [3- (4-Phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -benzoic acid ethyl ester

Compound 122:
Ethyl-carbamic acid 4- {6- [3- (4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -phenyl ester

Compound 123:
1- [3- (4-Amino-3-methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 124:
1- [3- (2-Methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 125:
1-((R) -1-methyl-4-phenyl-butyl) -3- [3- (2,3,4-trimethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl]- urea

Compound 126:
1- (1-Methyl-4-phenyl-butyl) -3- [3- (1-propyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -urea

Compound 127:
1- {3- [1- (2-morpholin-4-yl-ethyl) -1H-pyrazol-4-yl] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl) -Butyl) -urea

Compound 128:
1- [3- (2-Ethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea

Compound 129:
1- [3- (3-Chloro-4-hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl)- urea

Compound 130:
1- [3- (2-Amino-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 131:
1- (4-Oxo-4-phenyl-butyl) -3- [3- (1-propyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -urea

Compound 132:
Carbonic acid ethyl ester 4- {6- [3- (4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -phenyl ester

Compound 133:
1- [3- (2-hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 134:
1- [3- (4-Hydroxy-cyclohexylamino) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 135:
2,2-Dimethyl-propionic acid 4- {6- [3- (4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -phenyl ester

Compound 137:
1- [3- (4-Methylsulfanyl-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 138:
1- [3- (3-Cyano-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 139:
1- (4-Phenyl-butyl) -3- [3- (3,4,5-trimethoxy-phenylamino) -pyrido [2,3-b] pyrazin-6-yl] -urea

Compound 140:
1- {3-[(S) -1- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl- Butyl) -urea

Compound 141:
1- [3- (3-Hydroxy-4,5-dimethoxy-phenylamino) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 142:
1- {3- [1- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl-butyl) -urea

Compound 144:
1- [3- (4-Fluoro-2-hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 145:
1- {3- [4-Methoxy-3- (morpholine-4-sulfonyl) -phenyl] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl-butyl) -urea

Compound 146:
1- [3- (2-Methoxy-pyridin-3-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 147:
1- [3- (4-Hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea

Compound 148:
1- [3- (3-Hydroxy-4-methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl)- urea

Compound 149:
1- (3-furan-3-yl-pyrido [2,3-b] pyrazin-6-yl) -3-((R) -1-methyl-4-phenyl-butyl) -urea

Compound 150:
1-((R) -1-methyl-4-phenyl-butyl) -3- (3-pyridin-3-yl-pyrido [2,3-b] pyrazin-6-yl) -urea

Compound 151:
1- [3- (3-Hydroxy-4-methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 152:
1- (3-furan-3-yl-pyrido [2,3-b] pyrazin-6-yl) -3- (4-phenyl-butyl) -urea

Compound 153:
1-((R) -1-methyl-4-phenyl-butyl) -3- [3- (4-methyl-piperazin-1-yl) -pyrido [2,3-b] pyrazin-6-yl]- urea

Compound 154:
1-((R) -1-methyl-4-phenyl-butyl) -3- (3-piperidin-1-yl-pyrido [2,3-b] pyrazin-6-yl) -urea

Compound 155:
1- [3- (1-Methyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 156:
1- [3- (4-Hydroxymethyl-2-methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -Urea

Compound 157:
1-((R) -1-methyl-4-phenyl-butyl) -3- (3-pyridin-4-yl-pyrido [2,3-b] pyrazin-6-yl) -urea

Compound 158:
1- [3- (3-Hydroxymethyl-2-methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -Urea

Compound 159:
1- (4-Phenyl-butyl) -3- [3- (1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -urea

Compound 160:
1- [3- (4-Hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 161:
1- [3- (2-Methoxy-pyridin-3-yl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl)- urea

Compound 162:
1- {3- [1- (3-hydroxy-propyl) -1H-pyrazol-4-yl] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl-butyl)- urea

Compound 163:
1- {3- [1- (2,2-difluoro-ethyl) -1H-pyrrol-3-yl] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl-butyl ) -Urea

Compound 164:
1- (1-Methyl-4-phenyl-butyl) -3- [3- (1-methyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -urea

Compound 165:
Phosphoric acid mono- (4- {6- [3- (4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -phenyl) ester

Compound 166:
1-((R) -1-methyl-4-phenyl-butyl) -3- (3-morpholin-4-yl-pyrido [2,3-b] pyrazin-6-yl) -urea

Compound 167:
1- [3- (4-Hydroxymethyl-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea

Compound 168:
1-((R) -1-methyl-4-phenyl-butyl) -3- {3- [1- (2-morpholin-4-yl-ethyl) -1H-pyrazol-4-yl] -pyrido [2 , 3-b] pyrazin-6-yl} -urea

Compound 169:
1- (4-Methyl-4-phenyl-pentyl) -3- [3- (1-methyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -urea

Compound 170:
1-((R) -1-methyl-4-phenyl-butyl) -3- [3- (1-propyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl ] -Urea

Compound 171:
1-((R) -1-methyl-4-phenyl-butyl) -3- [3- (1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -urea

Compound 172:
1- (4-Phenyl-butyl) -3- (3-pyrrolidin-1-yl-pyrido [2,3-b] pyrazin-6-yl) -urea

Compound 173:
1-((R) -1-methyl-4-phenyl-butyl) -3- (3-pyrrolidin-1-yl-pyrido [2,3-b] pyrazin-6-yl) -urea

Compound 174:
1- [3- (3-Fluoro-4-hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 175:
1- [3- (3-Hydroxymethyl-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 176:
1- (3-morpholin-4-yl-pyrido [2,3-b] pyrazin-6-yl) -3- (4-phenyl-butyl) -urea

Compound 177:
1- [3- (3,5-Dimethyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl -Butyl) -urea

Compound 178:
1- [3- (3,4-Dimethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 179:
1- [3- (2-Methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea

Compound 180:
1-((R) -1-methyl-4-phenyl-butyl) -3- [3- (1-methyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl ] -Urea

Compound 181:
1- [3- (3-Hydroxymethyl-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea

Compound 182:
1- [3- (4-Hydroxymethyl-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 183:
1- [3- (2,4-Dimethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea

Compound 184:
1- (4-Phenyl-butyl) -3- (3-pyridin-4-yl-pyrido [2,3-b] pyrazin-6-yl) -urea

Compound 185:
1- [3- (3-Fluoro-4-hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl)- urea

Compound 186:
1- [3- (3-Chloro-4-hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 187:
1- [3-((S) -3-Methyl-morpholin-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl -Butyl) -urea

Compound 188:
1- [3- (4- {2- [2- (2-hydroxy-ethoxy) -ethoxy] -ethoxy} -phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-(( R) -1-Methyl-4-phenyl-butyl) -urea

Compound 189:
1- {3- [1- (2-hydroxy-ethyl) -1H-pyrazol-4-yl] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl-butyl)- urea

Compound 194:
2-Methoxy-4- {6- [3- (4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -benzoic acid

Compound 195:
(S) -2-Amino-3- (4- {6- [3-((R) -1-methyl-4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazine-3- Yl} -phenyl) -propionic acid; hydrochloride

Compound 196:
3- {6- [3-((R) -1-methyl-4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -benzoic acid

Compound 197:
(S) -2-Amino-3- (4- {6- [3- (4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -phenyl) -propionic acid

Compound 198:
3- {6- [3- (4-Phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -benzoic acid

Compound 199:
1- {3- [4- (2-methoxy-ethoxy) -phenyl] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl-butyl) -urea

Compound 200:
rac 1- {3- [4- (2-hydroxy-propoxy) -phenyl] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl-butyl) -urea

Compound 201:
1- (3- {4- [2- (2-hydroxy-ethoxy) -ethoxy] -phenyl} -pyrido [2,3-b] pyrazin-6-yl) -3- (4-phenyl-butyl)- urea

Compound 202:
1- {3- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl-butyl) -urea

Compound 203:
1- [3- (3-Methoxymethyl-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea

Compound 204:
1- {3- [3- (2-methoxy-ethoxymethyl) -phenyl] -pyrido [2,3-b] pyrazin-6-yl} -3-((R) -1-methyl-4-phenyl- Butyl) -urea

Compound 205:
1- {3- [3- (2-Dimethylamino-ethoxymethyl) -phenyl] -pyrido [2,3-b] pyrazin-6-yl} -3-((R) -1-methyl-4-phenyl -Butyl) -urea

Compound 206:
Methanesulfonic acid 3- {6- [3-((R) -1-methyl-4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -benzyl ester

Compound 207:
1-((R) -1-methyl-4-phenyl-butyl) -3- {3- [3- (2-morpholin-4-yl-ethoxymethyl) -phenyl] -pyrido [2,3-b] Pyrazin-6-yl} -urea

Compound 208:
Ethyl-carbamic acid 3- {6- [3-((R) -1-methyl-4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -benzyl ester

からなる群から選択されるピリドピラジン化合物であって、哺乳動物における、ras-Raf-Mek-Erkシグナル伝達経路によって媒介される、生理学的および／または病態生理学的な状態の治療または予防のための医薬品の製造のために使用できる化合物の製造によって解決された。 Compound 209:
1-((R) -1-methyl-4-phenyl-butyl) -3- {3- [3-((2R, 3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- Hydroxymethyl-tetrahydro-pyran-2-yloxymethyl) -phenyl] -pyrido [2,3-b] pyrazin-6-yl} -urea

A pyridopyrazine compound selected from the group consisting of: a pharmaceutical for the treatment or prevention of a physiological and / or pathophysiological condition mediated by the ras-Raf-Mek-Erk signaling pathway in a mammal Has been solved by the production of compounds that can be used for the production of

  To avoid ambiguity, a chemical structure shall clearly define a specific explicit compound when the chemical structure and chemical name of the explicit compound above do not coincide with each other by mistake. .

  The above mentioned generic compounds having the general formula (I) and preferred embodiments and the explicitly identified pyridopyrazine compounds 90-189, 194-209 are collectively referred to below as “compounds according to the invention”.

  The expressions and terms specified to describe the compounds according to the invention having general formula (I), preferred embodiments and compounds 90 to 189, 194 to 209 are not specifically described in the detailed description and claims. As long as it basically has the following meaning.

In the context of the present invention, the expression “alkyl” is an acyclic saturated or unsaturated hydrocarbon group which may be branched or straight chain and contains 1 to 8 carbon atoms. Including said groups having C ₁ -C ₈ -alkanyl, C ₂ -C ₈ -alkenyl and C ₂ -C ₈ -alkynyl. Alkenyl has at least one C—C double bond and alkynyl has at least one C—C triple bond. Alkynyl may additionally have at least one C—C double bond. Preferred alkyl groups are methyl, ethyl, n-propyl, 2-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 2-hexyl, n-heptyl, n - octyl, n- nonyl, n- decyl, n- undecyl, n- dodecyl, Echirueniru (vinyl), ethynyl, propenyl _{(-CH 2 CH = CH 2;} -CH = CH-CH 3, -C (= CH 2 ) —CH ₃ ), propynyl (—CH ₂ —C≡CH, —C≡C—CH ₃ ), butenyl, butynyl, pentenyl, pentynyl, hexenyl, hexynyl, heptenyl, heptynyl, octenyl, octadienyl and octynyl.

For the purposes of the present invention, the expression “cycloalkyl” is a cyclic non-aromatic carbonization having 1 to 3 rings, preferably 3 to 20, preferably 3 to 12 carbon atoms. a hydrogen, the may be saturated or unsaturated hydrocarbons, more preferably C ₃ -C ₈ - means a cycloalkyl. Cycloalkyl groups can be part of a bicyclic or polycyclic system, for example, a cycloalkyl group can be any possible, as defined herein, aryl, heteroaryl or heterocyclyl group. It may be fused with one or more desired ring members. The coupling to the compound of general formula (I) can be effected via any possible ring member of the cycloalkyl group. Preferred cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclohexenyl, cyclopentenyl and cyclooctadienyl.

  The expression “heterocyclyl” is a 3- to 14-membered, preferably 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered cyclic organic group, wherein at least one heteroatom, optionally Represents said organic group containing 2, 3, 4 or 5 heteroatoms, in particular nitrogen, oxygen and / or sulfur, wherein said heteroatoms are identical or different and said cyclic group is Saturated or unsaturated but not aromatic. A heterocyclyl group may be part of a bicyclic or polycyclic system, for example, a heterocyclyl group may be any possible and desired aryl, heteroaryl or cycloalkyl group as defined herein. May be condensed with one or more ring members. The coupling to the compound of general formula (I) can be effected via any possible ring member of the heterocyclyl group. Preferred heterocyclyl groups are tetrahydrofuryl, pyrrolidinyl, imidazolidinyl, thiazolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiapyrrolidinyl, oxapiperazinyl, oxapiperidinyl and oxadiazolyl.

  In the context of the present invention, the expression “aryl” means an aromatic hydrocarbon having 3 to 14 carbon atoms, preferably 5 to 14, more preferably 6 to 14 carbon atoms. Said aryl group may also be part of a bicyclic or polycyclic system, in which case, for example, said aryl group is a heterocyclyl group, heteroaryl group or cycloalkyl group as defined herein. To any possible and desired ring member, for example, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, thiazolidine, tetrahydropyran, dihydropyran, piperidine, furan, thiophene, imidazole, thiazole, oxazole, isoxazole. And condensed. The coupling to the compound of general formula (I) can be effected via any possible ring member of the aryl group. Preferred aryl groups are phenyl, biphenyl, naphthyl and anthracenyl, but likewise indanyl, indenyl or 1,2,3,4-tetrahydronaphthyl.

  The expression “heteroaryl” means at least one heteroatom, optionally 2, 3, 4 or 5 heteroatoms, in particular a 5-, 6- or 7-membered ring containing nitrogen, oxygen and / or sulfur. Represents an aromatic group of the formula, wherein the heteroatoms are the same or different. The number of nitrogen atoms is preferably 0 to 3, and the number of oxygen atoms and sulfur atoms is preferably 0 or 1. A heteroaryl group may be part of a bicyclic or polycyclic system, for example, a heteroaryl group may be any of the possible heterocyclyl, aryl or cycloalkyl groups defined herein and It may be fused with one or more desired ring members. The coupling to the compound of general formula (I) can be effected via any possible ring member of the heteroaryl group. Preferred heteroaryl groups are pyrrolyl, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazole, tetrazole, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, phthalazinyl, indolyl, indazolyl, indolizinyl, indolizinyl, Quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, carbazolyl, phenazinyl, phenoxazinyl, phenothiazinyl and acridinyl.

For the purposes of the present invention, the expressions “alkyl-cycloalkyl”, “cycloalkylalkyl”, “alkyl-heterocyclyl”, “heterocyclylalkyl”, “alkyl-aryl”, “arylalkyl”, “alkyl-heteroaryl” “And“ heteroarylalkyl ”are alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, respectively, as defined above, and said cycloalkyl, heterocyclyl, aryl and heteroaryl groups are of the general formula ( It means that it is bound to the compound of I) via an alkyl group, preferably via a C ₁ -C ₈ -alkyl group, more preferably via a C ₁ -C ₅ -alkyl group.

Related to “alkyl”, “cycloalkyl”, “heterocyclyl”, “aryl”, “heteroaryl”, “alkyl-cycloalkyl”, “alkyl-heterocyclyl”, “alkyl-aryl” and “alkyl-heteroaryl” In the meaning of the present invention, the term “substituted” means that one or more hydrogen atoms may be substituted with F, Cl, _{br, I, CN, CF 3} , NH 2, NH- alkyl, NH- aryl, N _{(alkyl) 2, NO 2, SH,} S- alkyl, SO ₂ - _{alkyl, OH, OCHF 2, OCF 3} , OMe, OEt, O—CH ₂ —CH ₂ —OMe; O—CH ₂ —CH ₂ —OH; O—CH ₂ —CH ₂ —O—CH ₂ —CH ₂ —OMe; O—CH ₂ —CH ₂ —NMe ₂ ; O CH ₂ -CH ₂ - morpholinyl; O-alkyl - aryl, O- aryl, -O-CH-O-; O -C (O) -NHEt; OSO 2 Me, OSO 3 H, OP (O) (OH) It is understood to be substituted by ₂ , CHO, CO ₂ H, SO ₃ H, alkyl, alkyl-OH or 4-methyl-piperazin-1-ylmethyl. The substituents can be the same or different, and the substitution can be made at any arbitrary and possible position of the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups.

  In the context of the present invention, the expression “halogen” includes the halogen atoms fluorine, chlorine, bromine and iodine.

Multiple substituted groups are multiple, eg double, triple, identical as groups substituted with either different atoms or identical atoms, eg as in CF ₃ , —CH ₂ CF _3. As a group substituted in triplicate with the carbon atom of or a group substituted at different positions such as in the case of —CH (OH) —CH═CH—CHCl ₂ . Multiple substitutions can be made with the same or different substituents.

  As long as the compounds according to the invention have at least one asymmetric center, they are in their racemic form, in pure enantiomers and / or diastereomers, or in their enantiomers and / or diastereomers. May be present in the form of a mixture of The mixture can exist in any mixture ratio of stereoisomers.

  Thus, for example, a compound according to the invention which has one or more chiral centers and exists as its racemate is known per se to its optical isomers, ie to enantiomers or diastereomers. It can be separated by a method. Said separation may be by column separation in a chiral phase, by recrystallization from an optically active solvent, or by using an optically active acid or base, or an optically active reagent such as an optically active alcohol. The derivatization used can be followed by subsequent separation of the residue.

  The compounds according to the invention may exist in the form of their double bond isomers, as “pure” E isomers or Z isomers, or in the form of mixtures of these double bond isomers.

  If possible, the compounds according to the invention can exist in tautomeric forms.

  When the compound has a sufficiently basic group, such as a primary amine, secondary amine or tertiary amine group, the compound according to the invention uses inorganic and organic acids, It can be converted into their physiologically acceptable salts. The pharmaceutically acceptable salts of the compounds according to the invention are preferably hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid, trifluoroacetic acid, sulfoacetic acid. , Oxalic acid, malonic acid, maleic acid, succinic acid, tartaric acid, racemic acid, malic acid, embonic acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid or aspartic acid. Among the salts formed are hydrochloride, hydrobromide, sulfate, hydrogen sulfate, phosphate, methanesulfonate, tosylate, carbonate, bicarbonate, formate, acetate , Trifluoromethanesulfonate, sulfoacetate, oxalate, malonate, maleate, succinate, tartrate, malate, embonate, mandelate, fumarate, lactate, citric acid Salt, glutamate and aspartate. The stoichiometry of the salt formed of the compound according to the invention may be an integer multiple of 1 or a non-integer multiple of 1.

  If the compound has a sufficiently acidic group, such as a carboxy group, the compounds according to the invention are converted into their physiologically acceptable salts using inorganic and organic bases. be able to. Possible inorganic bases are, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, and possible organic bases are ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dibenzylethylenediamine and lysine. The stoichiometry of the salt formed of the compound according to the invention may be an integer multiple of 1 or a non-integer multiple of 1.

  Preference is likewise given to solvates, in particular hydrates, of the compounds according to the invention, which can be obtained, for example, by crystallization from a solvent or an aqueous solution. In this context, one, two, three or any number of solvent molecules or water molecules can be combined with the compounds according to the invention to form solvates and hydrates.

  It is known that chemicals form solids that exist in various ordered states called polymorphs or polymorphic transformations. The various transformations of polymorphic substances can vary greatly in terms of their physical properties. The compounds according to the invention can exist in various polymorphs, in which case certain modifications may be transferable.

  The compounds according to the invention can likewise be present in any prodrug form, for example in the form of esters, carbonates, carbamates, ureas, amides or phosphates, in which the actually biologically active form is Released only by catabolism.

  In addition, it is known that chemicals are converted into metabolites in the body, which metabolites can also induce the desired biological action, possibly even in different forms. Yes.

  The corresponding prodrugs and metabolites of the compounds according to the invention should also be regarded as relevant to the present invention.

  Surprisingly and preferably here, it is ascertained that the compounds according to the invention can simultaneously exert, or have either, a modulating or inhibiting effect on one or more signal transduction pathways or enzymes. It was. In this context, it has been found that the compounds according to the invention are capable of producing or having a modulatory or inhibitory effect with high selectivity.

  The surprisingly favorable effect of the compounds according to the invention is in a physiological and / or pathophysiological state or clinical picture susceptible to or mediated by the treatment or modulation of one or more signaling pathways Allows a multi-therapy approach to be performed.

  More surprisingly and preferably, the compounds according to the invention can bring about or have a high selectivity on the ras-Raf-Mek-Erk signal transduction pathway or on the enzymes or the modulatory or inhibitory action. It was confirmed that the multiple mechanisms of action and therapeutic approaches described above could also be used with this signaling pathway or enzyme, “compounds 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 137, 138 139, 140, 141, 142, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164 , 165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189 , 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208 and / or a compound 209 "and / or a drug of at least one compound A physically effective amount, and optionally pharmaceutically acceptable excipients and / or auxiliaries. And is included within the scope of the present invention.

  The term “modulation” is understood according to the invention as the following “activation, partial activation, inhibition, partial inhibition”. In this case, such activation, partial activation, inhibition, partial inhibition should be measured and determined by ordinary measurement methods and determination methods, within the expertise of the average person skilled in the art. Thus, partial activation can be measured and determined for complete activation, as well as partial inhibition can be measured and determined for complete inhibition.

  The term “inhibit, inhibit and / or delay” is understood according to the invention as “partially or completely inhibit, partially or completely inhibit and / or delay” below. In this case, such inhibition, inhibition and / or delay should be measured and determined by conventional measurement and determination methods within the average expert knowledge of the person skilled in the art. Thus, for example, partial inhibition, partial inhibition and / or delay can be measured and determined relative to complete inhibition, complete inhibition and / or delay.

  The terms “modulation” and “inhibit, inhibit and / or delay” are within the scope of the present invention with respect to “enzyme” and / or “kinase” and are inactive forms (enzymatically inactive) of the respective enzyme and / or kinase. Activity) and / or active form (enzymatically active). This means that, within the scope of the present invention, the compounds according to the invention can have a modulatory action on the inactive, active or both forms of the enzyme and / or kinase.

  In a further aspect, the above object of the present invention is surprisingly applicable to the manufacture of a medicament for the treatment or prevention of physiological and / or pathophysiological conditions in mammals, Treatment or prevention has been solved by preparing compounds according to the invention which are carried out by modulation of the ras-Raf-Mek-Erk signaling pathway.

  In a further aspect, the subject of the invention described above is surprisingly a physiological and / or pathophysiological condition mediated by the ras-Raf-Mek-Erk signaling pathway in mammals. It has been solved by preparing a compound according to the invention which can be used for the manufacture of a medicament for treatment or prevention.

  In a further aspect, the above object of the present invention is surprisingly applicable to the manufacture of a medicament for the treatment or prevention of physiological and / or pathophysiological conditions in mammals, Treatment or prevention has been solved by preparing compounds according to the invention which are carried out by modulation of the ras-Raf-Mek-Erk signaling pathway.

  In a preferred embodiment, the compound according to the invention is as described above, wherein the modulation of the ras-Raf-Mek-Erk signaling pathway is “tyrosine kinase, serine / threonine kinase, receptor tyrosine kinase, cytoplasmic tyrosine kinase” Manufactured for use by modulation of one or more enzymes selected from the group consisting of "cytoplasmic serine / threonine kinases", preferably selected from the group consisting of "Erk, Erk1, Erk2" .

  In a further aspect, the above object of the present invention is surprisingly applicable to the manufacture of a medicament for the treatment or prevention of physiological and / or pathophysiological conditions in mammals, A compound in which treatment or prevention is effected by the modulation of one or more enzymes has been solved by making according to said aspects, preferred embodiments and said uses.

  In a further preferred embodiment, the compounds according to the invention are prepared for said use, wherein said modulation is inhibition.

  The compounds according to the invention can be administered for the treatment and / or prophylaxis within the scope of the invention to all known mammals, in particular humans.

  In another preferred embodiment, the compounds according to the invention are prepared for said use, wherein said mammal is “human, domestic animal, cow, pet, beef cattle, dairy cow, sheep, pig, goat” , Horse, pony, donkey, chick, camel, hare, rabbit, cat, dog, guinea pig, hamster, rat, mouse ", preferably a human.

  The compounds according to the invention can be used for the treatment and / or prevention of all known physiological and / or pathophysiological conditions within the scope of the invention.

  In a preferred embodiment, the compounds according to the invention are prepared for said use, wherein said physiological and / or pathophysiological state is “malignant tumor, benign tumor, inflammatory disease, Inflammation, pain, rheumatic disease, arthritic disease, HIV infection, neurological or neurodegenerative disease, rheumatoid arthritis, AIDS, ARC (AIDS related syndrome), Kaposi's sarcoma, brain and / or nervous system and / or meninges Derived tumor, dementia, Alzheimer's disease, hyperproliferative disease, psoriasis, endometriosis, scarring, benign prostatic hypertrophy (BPH), immune system disease, autoimmune disease, immunodeficiency disease, colon tumor, stomach tumor, Intestinal tumor, lung tumor, pancreatic tumor, ovarian tumor, prostate tumor, leukemia, melanoma, liver tumor, kidney tumor, head tumor, pharyngeal tumor, glioma, breast tumor, uterine cancer, Endometrial cancer, uterine vaginal carcinoma, brain tumor, adenocarcinoma, bladder cancer, stomach tumor, colorectal tumor, esophageal cancer, gynecological tumor, ovarian tumor, thyroid cancer, lymphoma, chronic leukemia, acute leukemia, restenosis, Diabetes mellitus, diabetic nephropathy, fibrosis, cystic fibrosis, malignant nephrosclerosis, thrombotic microvascular syndrome, organ transplant rejection, glomerulopathy, metabolic disease, solid / fixed tumor, rheumatoid arthritis, diabetic Retinopathy, asthma, allergy, allergic disease, chronic obstructive pulmonary disease, inflammatory bowel disease, fibrosis, atherosclerosis, heart disease, cardiovascular disease, myocardial disease, vascular disease, angiogenic disease , Kidney disease, rhinitis, Graves disease, local ischemia, heart failure, ischemia, cardiac hypertrophy, renal failure, cardiomyocyte dysfunction, hypertension, vasoconstriction, stroke attack, anaphylactic shock, platelet aggregation reaction, skeletal muscle atrophy, obesity Overweight , Glucose homeostasis (glucosis homeostasis), congestive heart failure, angina, heart attack, myocardial infarction, hyperglycemia, hypoglycemia is selected from the group consisting of hypertension ".

  In a further aspect of the present invention, the above-mentioned object of the present invention is surprisingly used in the manufacture of a medicament for the treatment or prevention of physiological and / or pathophysiological conditions in mammals. For the preparation of said compound, wherein said medicament comprises at least one further pharmacologically active substance according to said aspect, preferred embodiments and said use.

  In a further aspect of the present invention, the above-mentioned object of the present invention is surprisingly used in the manufacture of a medicament for the treatment or prevention of physiological and / or pathophysiological conditions in mammals. A compound for administration in which said medicament is administered together with at least one further pharmacologically active substance before and / or during treatment and / or after treatment, Solved by manufacturing according to the aspects, preferred embodiments and uses described above.

  In a further aspect of the present invention, the above-mentioned object of the present invention is surprisingly used in the manufacture of a medicament for the treatment or prevention of physiological and / or pathophysiological conditions in mammals. A compound for administration, wherein said medicament is administered before and / or during and / or after radiation therapy and / or surgery. Solved by manufacturing according to.

  Within the scope of the present invention, the compounds according to the invention can be administered together with any known pharmacologically effective substance in the combination therapy described above.

  In a preferred embodiment, the compounds according to the invention are prepared for the aforementioned use, wherein the further pharmacologically active substances are “DNA topoisomerase I and / or II inhibitors, DNA intercalators, From the group consisting of alkylating agents, microtubule destabilizing factors, hormones and / or growth factor receptor agonists and / or antagonists, growth factors and antibodies to those receptors, kinase inhibitors, alkylphospholipids, antimetabolites Selected.

  In a preferred embodiment, the compounds according to the invention are prepared for the above-mentioned use, wherein further pharmacologically active substances are “asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, cholaspase” (Colaspase), cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycin), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechloretamine, 6 -Mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifene, strept Tozosin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine, vindesine, aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine cladribine, busulfan, diethylstilbestrol, 2 ', 2'-difluorodeoxycytidine, docetaxel, erythro Hydroxynonyl adenine, ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate , Melphalan, mitotane, paclitaxel, oxaliplatin, pentostatin, N Phosphonoacetyl-L-aspartate (PALA), pricamycin, semstin, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, vinorelbine, epothilone, gemcitabine, taxotere, BCNU, CCNU, DTIC, 5-fluorouracil, Herceptin, Selected from the group consisting of Avastin, Erbitux, Sorafenib, Gleevec, Iressa, Tarceva, rapamycin, perifosine, miltefosine, edelfosine, actinomycin D ".

  Oral administration can be carried out, for example, in solid form as tablets, capsules, gel capsules, dragees, granules or powders, but also in the form of drinking solutions. For oral administration, the novel compounds according to the invention as defined above are commonly used physiologically acceptable auxiliaries and excipients such as gum arabic, talc, starch, sugars such as mannitol. , Methylcellulose, lactose, gelatin, surfactant, magnesium stearate, cyclodextrin, aqueous or non-aqueous excipients, diluents, dispersants, emulsifiers, lubricants, preservatives and flavoring (eg ether oils) Can be combined. The compounds according to the invention can also be dispersed in a microparticle composition, for example a nanoparticle composition.

  Parenteral administration can be carried out, for example, by intravenous, subcutaneous or intramuscular injection of sterile aqueous or oily solutions, suspensions or emulsions, by implants, or by ointments, creams or suppositories. it can. Optionally, administration can be performed as a delayed form. The implant may comprise an inert material such as a biodegradable polymer or a synthetic silicone such as silicone rubber. Intravaginal administration can be performed, for example, by a vaginal ring. Intrauterine administration can be performed, for example, using a diaphragm or other suitable intrauterine device. In addition, transdermal administration can be provided using formulations and / or suitable means, particularly plasters, which are particularly suitable for this purpose.

  As already explained, the novel compounds according to the invention can also be combined with further pharmaceutically active substances. In the combination therapy framework, the individual active ingredients can be administered simultaneously or separately, by the same route (eg, oral) or by separate routes (eg, oral and as an injection). They can be present or administered in the same or different amounts in a unit dose. A particular dosing regime can be applied if it appears suitable. Thus, a plurality of novel compounds according to the invention can be combined with one another.

  The dosage may vary over a wide range according to the type of indication, the severity of the disease, the mode of administration, the age, the sex, the body weight and the sensitivity of the subject to be treated. Within the abilities of those skilled in the art, the “pharmacologically effective amount” of the combined pharmaceutical composition should be determined. Administration can be carried out in a single dose or in multiple individual doses.

  Suitable unit doses are from 0.001 mg to 100 mg of active substance per kg patient body weight, ie at least one compound according to the invention and optionally further pharmaceutically active substances.

  In a further aspect of the invention, therefore, “compounds 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 137, 138, 139, 140, 141, 142, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208 and / or a pharmacologically effective amount of at least one compound selected from the group consisting of compound 209 "and optionally pharmaceutically acceptable Pharmaceutical compositions comprising sex excipients and / or auxiliaries are within the scope of the present invention.

  Preferred, particularly preferred pharmaceutical compositions are those comprising at least one of the preferred compounds according to the invention. The pharmaceutical composition according to the invention may comprise, in addition to the at least one compound according to the invention as defined above, at least one further pharmaceutically active substance as described in detail above.

  The pharmaceutical composition according to the invention allows at least one novel compound according to the invention as defined above to be administered in a pharmacologically effective amount, preferably in a unit dose, for example in the unit dose as described above, preferably orally. Contained in the dosage form.

  With respect to pharmaceutical compositions comprising the compounds according to the invention, and with respect to the use of the compounds according to the invention as pharmaceuticals, reference is made to the explanations made regarding the possibilities for use and administration with respect to the use of the novel compounds themselves according to the invention.

  In a further aspect of the present invention, the object of the present invention is, surprisingly, the pharmacologically effective amount of at least one preferred compound according to the invention as defined above and at least one of the above definitions. Solved by the manufacture of a kit comprising a pharmacologically effective amount of a further pharmacologically effective substance.

  The nomenclature of the compounds according to the invention having the general formula (I) using the preferred exemplary embodiment, in particular AutoNom 2000 software (ISIS ™ / Draw 2.5; MDL) together with compounds 90-189, 194-209 I went.

General synthetic method for compounds according to the invention The procedure for the preparation of substituted pyrido [2,3-b] pyrazine according to the invention is described below.

The compounds according to the invention can be obtained according to corresponding procedures known to those skilled in the art. Furthermore, for the preparation of the compounds according to the invention, reference is made to the patent specifications WO 2004/104002, WO 2004/104003, WO2007 / 054556 and WO 2008/138878 or corresponding methods known from the literature. For the preparation according to the invention of initial compounds, intermediate compounds and pyridopyrazine, reference is made in particular to the following main documents: Its content should now be an integral part of the present disclosure:

  The present invention will be described in detail with reference to the following examples, but is not limited to these examples.

融点：１４２℃ Example compound 90:
1- [3- (4- {2- [2- (2-hydroxy-ethoxy) -ethoxy] -ethoxy} -phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4 -Phenyl-butyl) -urea

Melting point: 142 ° C

融点：２９９〜３００℃ Compound 91:
1- [3- (3,5-Dimethyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Melting point: 299-300 ° C

融点：１３５〜１３８℃ Compound 92:
1- (4-Phenyl-butyl) -3- [3- (2,3,4-trimethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -urea

Melting point: 135-138 ° C

融点：１８１〜１８３℃ Compound 93:
1- [3- (4-Methyl-piperazin-1-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Melting point: 181-183 ° C

融点：２２６℃ Compound 94:
1- [3- (3H-Benzimidazol-5-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Melting point: 226 ° C

融点：２００〜２０３℃ Compound 95:
1- [3- (3-Amino-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Melting point: 200-203 ° C

融点：２０９〜２１１℃ Compound 96:
1- (4-Phenyl-butyl) -3- (3-piperazin-1-yl-pyrido [2,3-b] pyrazin-6-yl) -urea; hydrochloride

Melting point: 209-211 ° C

融点：２０２〜２０４℃ Compound 97:
1- [3- (1-Methyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-p-tolyl-butyl) -urea

Melting point: 202-204 ° C

融点：１９５〜１９７℃ Compound 98:
1- [3- (3,4-Dimethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea

Melting point: 195-197 ° C

融点：１９７〜２００℃ Compound 99:
1- [4- (4-Fluoro-phenyl) -butyl] -3- [3- (1-methyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl]- urea

Melting point: 197-200 ° C

融点：２０５〜２０７℃ Compound 100:
1- (4-Methyl-4-phenyl-pentyl) -3- [3- (1-propyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -urea

Melting point: 205-207 ° C

融点：２００〜２０３℃ Compound 101:
1- [3- (2,4-Dimethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Melting point: 200-203 ° C

融点：１７３〜１７５℃ Compound 102:
1- [3- (2-Ethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Melting point: 173-175 ° C

融点：２７１〜２７３℃ Compound 103:
1- [3- (3,5-Dichloro-4-hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Melting point: 271-273 ° C

融点：２２６〜２２８℃ Compound 104:
1- [3- (3-Hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Melting point: 226-228 ° C

融点：２８０℃（分解） Compound 105:
1- (4-Phenyl-butyl) -3- [3- (2H-pyrazol-3-yl) -pyrido [2,3-b] pyrazin-6-yl] -urea

Melting point: 280 ° C. (decomposition)

融点：２０７〜２１０℃ Compound 106:
1- [3- (4-Hydroxy-2-methyl-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Melting point: 207-210 ° C

融点：２２０℃ Compound 107:
Acetic acid 4- {6- [3- (4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -phenyl ester

Melting point: 220 ° C

融点：２０７〜２０８℃ Compound 108:
1- [3- (1-Ethyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Melting point: 207-208 ° C

融点：２３８〜２４１℃ Compound 109:
1- [3- (3-Bromo-4-hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Melting point: 238-241 ° C

Compound 110:
1- (4-Phenyl-butyl) -3- (3-pyridin-3-yl-pyrido [2,3-b] pyrazin-6-yl) -urea

融点：２３０〜２３３℃ Compound 111:
1- [3- (1-Methyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (1,2,3,4-tetrahydro-naphthalene-2 -Ylmethyl) -urea

Melting point: 230-233 ° C

融点：１５０〜１５３℃ Compound 112:
1- [3- (2,3-Dimethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea

Melting point: 150-153 ° C

融点：２２４〜２２６℃ Compound 113:
1- [3- (5-Methyl-1-phenyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Melting point: 224-226 ° C

Compound 114:
1- [3- (1-Butyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

融点：１９５〜１９６℃ Compound 115:
1- [4- (4-Methoxy-phenyl) -butyl] -3- [3- (1-methyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl]- urea

Melting point: 195-196 ° C

融点：２４３℃（分解） Compound 116:
1- (4-Phenyl-butyl) -3- [3- (piperidin-4-ylamino) -pyrido [2,3-b] pyrazin-6-yl] -urea

Melting point: 243 ° C (decomposition)

Compound 117:
1- (4-Phenyl-butyl) -3- {3-[(pyridin-4-ylmethyl) -amino] -pyrido [2,3-b] pyrazin-6-yl} -urea

融点：２００〜２０３℃ Compound 118:
1- [3- (4-Methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Melting point: 200-203 ° C

融点：１１８〜１２０℃ Compound 119:
1- (4-Phenyl-butyl) -3- (3-propylamino-pyrido [2,3-b] pyrazin-6-yl) -urea

Melting point: 118-120 ° C

融点：１５８〜１６０℃ Compound 120:
1- (4-Phenyl-butyl) -3- (3-o-tolyl-pyrido [2,3-b] pyrazin-6-yl) -urea

Melting point: 158-160 ° C

融点：１９０〜１９１℃ Compound 121:
3- {6- [3- (4-Phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -benzoic acid ethyl ester

Melting point: 190-191 ° C

融点：１９８℃ Compound 122:
Ethyl-carbamic acid 4- {6- [3- (4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -phenyl ester

Melting point: 198 ° C

Compound 123:
1- [3- (4-Amino-3-methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

融点：１７３〜１７７℃ Compound 124:
1- [3- (2-Methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Melting point: 173-177 ° C

融点：１２３〜１２５℃ Compound 125:
1-((R) -1-methyl-4-phenyl-butyl) -3- [3- (2,3,4-trimethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl]- urea

Melting point: 123-125 ° C

融点：１６６〜１６８℃ Compound 126:
1- (1-Methyl-4-phenyl-butyl) -3- [3- (1-propyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -urea

Melting point: 166-168 ° C

融点：１９０〜１９３℃ Compound 127:
1- {3- [1- (2-morpholin-4-yl-ethyl) -1H-pyrazol-4-yl] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl) -Butyl) -urea

Melting point: 190-193 ° C

融点：１４４〜１４６℃ Compound 128:
1- [3- (2-Ethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea

Melting point: 144-146 ° C

融点：２２５〜２２８℃ Compound 129:
1- [3- (3-Chloro-4-hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl)- urea

Melting point: 225-228 ° C

融点：１９０〜１９１℃ Compound 130:
1- [3- (2-Amino-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Melting point: 190-191 ° C

融点：２１０〜２１１℃ Compound 131:
1- (4-Oxo-4-phenyl-butyl) -3- [3- (1-propyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -urea

Melting point: 210-211 ° C

融点：２１２℃ Compound 132:
Carbonic acid ethyl ester 4- {6- [3- (4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -phenyl ester

Melting point: 212 ° C

融点：２４７〜２４８℃ Compound 133:
1- [3- (2-hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Melting point: 247-248 ° C

融点：１４６℃（分解） Compound 134:
1- [3- (4-Hydroxy-cyclohexylamino) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Melting point: 146 ° C (decomposition)

融点：２２５℃ Compound 135:
2,2-Dimethyl-propionic acid 4- {6- [3- (4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -phenyl ester

Melting point: 225 ° C

融点：２２７〜２３０℃ Compound 137:
1- [3- (4-Methylsulfanyl-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Melting point: 227-230 ° C

融点：２３７〜２４０℃ Compound 138:
1- [3- (3-Cyano-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Melting point: 237-240 ° C

融点：２２３〜２２５℃ Compound 139:
1- (4-Phenyl-butyl) -3- [3- (3,4,5-trimethoxy-phenylamino) -pyrido [2,3-b] pyrazin-6-yl] -urea

Melting point: 223-225 ° C

融点：１８２〜１８４℃ Compound 140:
1- {3-[(S) -1- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl- Butyl) -urea

Melting point: 182-184 ° C

融点：１３６〜１３９℃ Compound 141:
1- [3- (3-Hydroxy-4,5-dimethoxy-phenylamino) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Melting point: 136-139 ° C

融点：１８５〜１８７℃ Compound 142:
1- {3- [1- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl-butyl) -urea

Melting point: 185-187 ° C

融点：２４８〜２４９℃ Compound 144:
1- [3- (4-Fluoro-2-hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Melting point: 248-249 ° C

融点：２５６〜２５８℃ Compound 145:
1- {3- [4-Methoxy-3- (morpholine-4-sulfonyl) -phenyl] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl-butyl) -urea

Melting point: 256-258 ° C

融点：１９４〜１９７℃ Compound 146:
1- [3- (2-Methoxy-pyridin-3-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Melting point: 194-197 ° C

融点：２２６〜２２９℃ Compound 147:
1- [3- (4-Hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea

Melting point: 226-229 ° C

融点：１９６〜１９８℃ Compound 148:
1- [3- (3-Hydroxy-4-methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl)- urea

Melting point: 196-198 ° C

融点：２１８〜２２０℃ Compound 149:
1- (3-furan-3-yl-pyrido [2,3-b] pyrazin-6-yl) -3-((R) -1-methyl-4-phenyl-butyl) -urea

Melting point: 218-220 ° C

融点：２１８〜２２０℃ Compound 150:
1-((R) -1-methyl-4-phenyl-butyl) -3- (3-pyridin-3-yl-pyrido [2,3-b] pyrazin-6-yl) -urea

Melting point: 218-220 ° C

融点：２３０〜２３２℃ Compound 151:
1- [3- (3-Hydroxy-4-methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Melting point: 230-232 ° C

融点：２１２〜２１６℃ Compound 152:
1- (3-furan-3-yl-pyrido [2,3-b] pyrazin-6-yl) -3- (4-phenyl-butyl) -urea

Melting point: 212-216 ° C

融点：１７２〜１７５℃ Compound 153:
1-((R) -1-methyl-4-phenyl-butyl) -3- [3- (4-methyl-piperazin-1-yl) -pyrido [2,3-b] pyrazin-6-yl]- urea

Melting point: 172-175 ° C

融点：１７１〜１７４℃ Compound 154:
1-((R) -1-methyl-4-phenyl-butyl) -3- (3-piperidin-1-yl-pyrido [2,3-b] pyrazin-6-yl) -urea

Melting point: 171-174 ° C

融点：１９８〜２０１℃ Compound 155:
1- [3- (1-Methyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Melting point: 198-201 ° C

融点：１６８〜１７０℃ Compound 156:
1- [3- (4-Hydroxymethyl-2-methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -Urea

Melting point: 168-170 ° C

融点：２２３〜２２６℃ Compound 157:
1-((R) -1-methyl-4-phenyl-butyl) -3- (3-pyridin-4-yl-pyrido [2,3-b] pyrazin-6-yl) -urea

Melting point: 223-226 ° C

融点：１６８〜１７０℃ Compound 158:
1- [3- (3-Hydroxymethyl-2-methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -Urea

Melting point: 168-170 ° C

融点：２３１〜２３２℃ Compound 159:
1- (4-Phenyl-butyl) -3- [3- (1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -urea

Melting point: 231-232 ° C

融点：２３３〜２３５℃ Compound 160:
1- [3- (4-Hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Melting point: 233-235 ° C

融点：１６１〜１６３℃ Compound 161:
1- [3- (2-Methoxy-pyridin-3-yl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl)- urea

Melting point: 161-163 ° C

融点：１８２〜１８４℃ Compound 162:
1- {3- [1- (3-hydroxy-propyl) -1H-pyrazol-4-yl] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl-butyl)- urea

Melting point: 182-184 ° C

Compound 163:
1- {3- [1- (2,2-difluoro-ethyl) -1H-pyrrol-3-yl] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl-butyl ) -Urea

融点：２０４〜２０８℃ Compound 164:
1- (1-Methyl-4-phenyl-butyl) -3- [3- (1-methyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -urea

Melting point: 204-208 ° C

融点：２０２℃ Compound 165:
Phosphoric acid mono- (4- {6- [3- (4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -phenyl) ester

Melting point: 202 ° C

融点：２０１〜２０３℃ Compound 166:
1-((R) -1-methyl-4-phenyl-butyl) -3- (3-morpholin-4-yl-pyrido [2,3-b] pyrazin-6-yl) -urea

Melting point: 201-203 ° C

融点：１８７〜１９０℃ Compound 167:
1- [3- (4-Hydroxymethyl-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea

Melting point: 187-190 ° C

融点：１７８〜１８０℃ Compound 168:
1-((R) -1-methyl-4-phenyl-butyl) -3- {3- [1- (2-morpholin-4-yl-ethyl) -1H-pyrazol-4-yl] -pyrido [2 , 3-b] pyrazin-6-yl} -urea

Melting point: 178-180 ° C

融点：２０８〜２１０℃ Compound 169:
1- (4-Methyl-4-phenyl-pentyl) -3- [3- (1-methyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -urea

Melting point: 208-210 ° C

融点：１８５〜１８８℃ Compound 170:
1-((R) -1-methyl-4-phenyl-butyl) -3- [3- (1-propyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl ] -Urea

Melting point: 185-188 ° C

融点：２７４〜２７６℃ Compound 171:
1-((R) -1-methyl-4-phenyl-butyl) -3- [3- (1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -urea

Melting point: 274-276 ° C

融点：２０４〜２０６℃ Compound 172:
1- (4-Phenyl-butyl) -3- (3-pyrrolidin-1-yl-pyrido [2,3-b] pyrazin-6-yl) -urea

Melting point: 204-206 ° C

融点：１８７〜１９０℃ Compound 173:
1-((R) -1-methyl-4-phenyl-butyl) -3- (3-pyrrolidin-1-yl-pyrido [2,3-b] pyrazin-6-yl) -urea

Melting point: 187-190 ° C

融点：２６９〜２７０℃ Compound 174:
1- [3- (3-Fluoro-4-hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Melting point: 269-270 ° C

融点：１９８〜２００℃ Compound 175:
1- [3- (3-Hydroxymethyl-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Melting point: 198-200 ° C

融点：２００〜２０２℃ Compound 176:
1- (3-morpholin-4-yl-pyrido [2,3-b] pyrazin-6-yl) -3- (4-phenyl-butyl) -urea

Melting point: 200-202 ° C

融点：２６６〜２６９℃ Compound 177:
1- [3- (3,5-Dimethyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl -Butyl) -urea

Melting point: 266-269 ° C

融点：２１０〜２１１℃ Compound 178:
1- [3- (3,4-Dimethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Melting point: 210-211 ° C

融点：１３７〜１３８℃ Compound 179:
1- [3- (2-Methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea

Melting point: 137-138 ° C

融点：２２５〜２２８℃ Compound 180:
1-((R) -1-methyl-4-phenyl-butyl) -3- [3- (1-methyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl ] -Urea

Melting point: 225-228 ° C

融点：１９３〜１９５℃ Compound 181:
1- [3- (3-Hydroxymethyl-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea

Melting point: 193-195 ° C

融点：２１３〜２１５℃ Compound 182:
1- [3- (4-Hydroxymethyl-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Melting point: 213-215 ° C

融点：９８〜１００℃ Compound 183:
1- [3- (2,4-Dimethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea

Melting point: 98-100 ° C

融点：２１９〜２２２℃ Compound 184:
1- (4-Phenyl-butyl) -3- (3-pyridin-4-yl-pyrido [2,3-b] pyrazin-6-yl) -urea

Melting point: 219-222 ° C

融点：２２０〜２２２℃ Compound 185:
1- [3- (3-Fluoro-4-hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl)- urea

Melting point: 220-222 ° C

融点：２４１〜２４３℃ Compound 186:
1- [3- (3-Chloro-4-hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Melting point: 241-243 ° C

Compound 187:
1- [3-((S) -3-Methyl-morpholin-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl -Butyl) -urea

Compound 188:
1- [3- (4- {2- [2- (2-hydroxy-ethoxy) -ethoxy] -ethoxy} -phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-(( R) -1-Methyl-4-phenyl-butyl) -urea

Compound 189:
1- {3- [1- (2-hydroxy-ethyl) -1H-pyrazol-4-yl] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl-butyl)- urea

融点：２２９〜２３３℃ Compound 194:
2-Methoxy-4- {6- [3- (4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -benzoic acid

Melting point: 229-233 ° C

Compound 195:
(S) -2-Amino-3- (4- {6- [3-((R) -1-methyl-4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazine-3- Yl} -phenyl) -propionic acid; hydrochloride

融点：２６１℃（分解） Compound 196:
3- {6- [3-((R) -1-methyl-4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -benzoic acid

Melting point: 261 ° C. (decomposition)

融点：２３０〜２３２℃ Compound 197:
(S) -2-Amino-3- (4- {6- [3- (4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -phenyl) -propionic acid

Melting point: 230-232 ° C

融点：２５４〜２５６℃ Compound 198:
3- {6- [3- (4-Phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -benzoic acid

Melting point: 254-256 ° C

融点：２２３〜２２４℃ Compound 200:
rac 1- {3- [4- (2-hydroxy-propoxy) -phenyl] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl-butyl) -urea

Melting point: 223-224 ° C

融点：１９２〜１９４℃ Compound 201:
1- (3- {4- [2- (2-hydroxy-ethoxy) -ethoxy] -phenyl} -pyrido [2,3-b] pyrazin-6-yl) -3- (4-phenyl-butyl)- urea

Melting point: 192-194 ° C

融点：１９１〜１９２℃ Compound 202:
1- {3- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl-butyl) -urea

Melting point: 191-192 ° C

Compound 203:
1- [3- (3-Methoxymethyl-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea

Compound 204: D-119421
1- {3- [3- (2-methoxy-ethoxymethyl) -phenyl] -pyrido [2,3-b] pyrazin-6-yl} -3-((R) -1-methyl-4-phenyl- Butyl) -urea

Evidence for kinase inhibition of compounds according to the invention Cell-free kinase assay (using ALPHA technology)
The inhibitory action of the compounds according to the invention was tested in enzyme assays against various serine / threonine kinases, tyrosine kinases and lipid kinases. A recombinant human kinase, for example a kinase such as Erk2, was used in this case as a fragment consisting of at least a functional kinase domain, partially shortened but partially truncated. A commercially available kinase protein (Proqinase, Upstate) was used as a recombinant fusion protein with GST (glutathione-S-transferase) or His tag. Depending on the type of substrate, various kinase reactions were quantified by using suitable ALPHA ™ beads (Perkin-Elmer).

Test substance testing is described in detail below for the Erk assay. Selected test results of the Erk2 alpha assay are shown below. For determination of IC ₅₀ values, potential inhibitor substances were investigated at 10 semi-log step concentrations from 3.16 nM to 100 μM.

a) MAPK-ALPHAs (eg Erk2): test substance, 0.625 ng Erk2 (# 14-173, Upstate), 10 μM ATP and 15 nM biotinylated MBP (myelin basic protein) substrate in 384 well Optiplate ( Perkin-Elmer) and incubated in a volume of 15 μl for 1 hour. Incubation was performed at a pH of 7.5 in a volume of 25 mM Tris, 10 mM MgCl ₂ , 0.1% Tween-20, 100 μM NaVO ₄ , 2 mM DTT. The kinase reaction was then stopped by the addition of 10 μl ALPHA bead mix (10 μg / ml, # 6760617 / Perkin-Elmer) and 25 mM Tris together with anti-phospho MBP antibody (320 pM, # 05-429 / Upstate) Incubated in 200 mM NaCl, 100 mM EDTA and 0.3% BSA and allowed to stand overnight.

  The next morning, fluorescence was detected in an Envision plate reader (Perkin-Elmer).

% Inhibition values per evaluation substance concentrations were calculated by using the following formula from the raw data measured by Envision plate reader:

Eight measurements were made for each control and two measurements were made on the substance sample. The 0% control is either free of ATP or substrate, and the 100% control (fully active kinase) contains no test substance. IC ₅₀ values were determined using GraphPadPrism.

The compounds according to the invention showed effective inhibition of the IC ₅₀ of Erk and PI3K up to 1 nM.

Table 1: Erk2 alpha kinase assay test results (IC ₅₀ [μM] at 10 μM ATP)

Cell assay: Test for antiproliferative activity (XTT assay)
The principle of this test is the mitochondrial nature of the tetrazolium dye XTT (sodium 3 '-[1- (phenylaminocarbonyl) -3,4-tetrazolium] -bis (4-methoxy-6-nitro) benzenesulfonic acid, Sigma). It is based on intracellular reduction to formazan dye by dehydrogenase. The dye is formed only by metabolically active cells and its photometric measurable intensity is a quantitative indicator for the presence of viable cells. Reduction of pigmentation by incubating cells and substances together is used as a parameter for antiproliferative effects.

The test tumor cell line (ATCC) is injected into a 96-well microtiter plate at a defined cell number (1250 cells / well for Hct116) and then in an incubator at 37 ° C., 5% CO ₂ and 95% air Incubate overnight at humidity. Test substances were prepared as stock solutions (10 mM) in DMSO. For the determination of EC ₅₀ values, potential inhibitor substances were added to the cells in semi-log serial dilutions resulting in a final concentration of 1.58 nM to 50 μM. The cell plates were then incubated in an incubator for about 48 hours at 37 ° C., 5% CO ₂ and 95% air humidity.

  For the detection reaction, the substrate XTT was mixed with PMS (N-methyldibenzopyrazine methyl sulfate, Sigma) and added to the cells, thus 325 μg XTT / ml and 2.5 μg PMS / A final concentration of ml was obtained. It was then incubated for 3 hours at 37 ° C. and 95% air humidity. The formazan salt formed by cellular dehydrogenase could then be quantified by absorption at 490 nm.

The % evaluation inhibition was evaluated by using the following formula from the value for the optical density measured at 490 nm in each case:

Eight measurements were made for each control and two measurements were made on the substance sample. The 0% control contains no cells and the 100% control (growth control) contains no test substance. EC ₅₀ values were determined using GraphPadPrism.

The compounds according to the invention showed a partially effective inhibition of cell proliferation with an EC ₅₀ value of less than 1 μM.

Table 2: XTT assay test results (EC ₅₀ [μM])

Claims (23)

Formula (I)

[Where:
The substituents R1, R2, X have the following meanings:
X is O,
R1 is
(I) substituted aryl,
The aryl group, one or more identical or different F, Cl, Br, I, CF 3, CN, NH 2, NH- alkyl, NH- cycloalkyl, NH- heterocyclyl, NH- aryl, NH- heteroaryl aryl, NH- alkyl - cycloalkyl, NH- alkyl - heterocyclyl, NH- alkyl - aryl, NH- alkyl - heteroaryl, NH- alkyl -NH _2, NH- alkyl -OH, N (alkyl) _2, NHC (O ) -Alkyl, NHC (O) -cycloalkyl, NHC (O) -heterocyclyl, NHC (O) -aryl, NHC (O) -heteroaryl, NHC (O) -alkyl-aryl, NHC (O) -alkyl- heteroaryl, NHSO ₂ - alkyl, NHSO ₂ - cycloalkyl, NHSO ₂ - heteroaryl Krill, NHSO ₂ - aryl, NHSO ₂ - heteroaryl, NHSO ₂ - alkyl - aryl, NHSO ₂ - alkyl - heteroaryl, NO _2, SH, S- alkyl, S- aryl, S- heteroaryl, OH, OCF ₃ O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl, O-alkyl-heteroaryl, O - alkyl _{-OH, O- (CH 2) n} -O, O - (- CH 2 -CH 2 -O-) n -CH 2 -CH 2 -OH, OC (O) - alkyl, OC (O) - Cycloalkyl, OC (O) -heterocyclyl, OC (O) -aryl, OC (O) -heteroaryl, OC (O) -alkyl-aryl OC (O) - alkyl - heteroaryl, OC (O) -NH- alkyl, OSO ₃ H, OSO ₂ - alkyl, OSO ₂ - cycloalkyl, OSO ₂ - heterocyclyl, OSO ₂ - aryl, OSO ₂ - heteroaryl, OSO ₂ - alkyl - aryl, OSO ₂ - alkyl - heteroaryl, OP (O) (OH) 2, C (O) - alkyl, C (O) - aryl, C (O) - heteroaryl, O-CO ₂ - alkyl, CO ₂ H, CO ₂ - alkyl, CO ₂ - cycloalkyl, CO ₂ - heterocyclyl, CO ₂ - aryl, CO ₂ - heteroaryl, CO ₂ - alkyl - cycloalkyl, CO ₂ - alkyl - heterocyclyl, CO ₂ - alkyl - aryl, CO ₂ - alkyl - _{heteroaryl, C (O) -NH 2,} C (O) NH- alkyl, C ( O) NH-cycloalkyl, C (O) NH-heterocyclyl, C (O) NH-aryl, C (O) NH-heteroaryl, C (O) NH-alkyl-cycloalkyl, C (O) NH-alkyl -Heterocyclyl, C (O) NH-alkyl-aryl, C (O) NH-alkyl-heteroaryl, C (O) N (alkyl) ₂ , C (O) N (cycloalkyl) ₂ , C (O) N _{(aryl) 2, C (O) N} ( heteroaryl) _2, SO- alkyl, SO- aryl, SO ₂ - alkyl, SO ₂ - heterocyclyl, SO ₂ - _{aryl, SO 2 NH 2, SO 2} NH- alkyl, SO ₂ NH- aryl, SO ₂ NH- heteroaryl, SO ₂ NH- alkyl - aryl, SO ₃ H, SO ₂ O- alkyl, SO ₂ O-aryl, SO ₂ O-alkyl - aryl , Alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, n may have a value of 0, 1, 2 or 3 and the alkyl substituents as defined above for those moieties, cycloalkyl Substituents, heterocyclyl substituents, aryl substituents, heteroaryl substituents, alkyl-cycloalkyl substituents, alkyl-heterocyclyl substituents, alkyl-aryl substituents and alkyl-heteroaryl substituents may also be further substituted,
(II) unsubstituted or substituted heteroaryl,
It said heteroaryl group is 1 or more identical or different F, Cl, Br, I, CF 3, CN, NH 2, NH- alkyl, NH- cycloalkyl, NH- heterocyclyl, NH- aryl, NH- heteroaryl, NH- alkyl - cycloalkyl, NH- alkyl - heterocyclyl, NH- alkyl - aryl, NH- alkyl - heteroaryl, NH- alkyl -NH _2, NH- alkyl -OH, N (alkyl) _2, NHC ( O) -alkyl, NHC (O) -cycloalkyl, NHC (O) -heterocyclyl, NHC (O) -aryl, NHC (O) -heteroaryl, NHC (O) -alkyl-aryl, NHC (O) -alkyl - heteroaryl, NHSO ₂ - alkyl, NHSO ₂ - cycloalkyl, NHSO ₂ - Heterocyclyl, NHSO ₂ - aryl, NHSO ₂ - heteroaryl, NHSO ₂ - alkyl - aryl, NHSO ₂ - alkyl - heteroaryl, NO _2, SH, S- alkyl, S- aryl, S- heteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl, O-alkyl-heteroaryl, OC (O)- Alkyl, OC (O) -cycloalkyl, OC (O) -heterocyclyl, OC (O) -aryl, OC (O) -heteroaryl, OC (O) -alkyl-aryl, OC (O) -alkyl-heteroaryl , OSO ₃ H, OSO ₂ - alkyl, OSO ₂ - cycloalkyl, OSO ₂ - Haitai Cyclyl, OSO ₂ - aryl, OSO ₂ - heteroaryl, OSO ₂ - alkyl - aryl, OSO ₂ - alkyl - heteroaryl, OP (O) (OH) 2, C (O) - alkyl, C (O) - aryl , C (O) - heteroaryl, CO ₂ H, CO ₂ - alkyl, CO ₂ - cycloalkyl, CO ₂ - heterocyclyl, CO ₂ - aryl, CO ₂ - heteroaryl, CO ₂ - alkyl - cycloalkyl, CO ₂ - alkyl - heterocyclyl, CO ₂ - alkyl - aryl, CO ₂ - alkyl - _{heteroaryl, C (O) -NH 2,} C (O) NH- alkyl, C (O) NH- cycloalkyl, C (O) NH -Heterocyclyl, C (O) NH-aryl, C (O) NH-heteroaryl, C (O) NH-alkyl-cycloalkyl, C (O) NH -Alkyl-heterocyclyl, C (O) NH-alkyl-aryl, C (O) NH-alkyl-heteroaryl, C (O) N (alkyl) ₂ , C (O) N (cycloalkyl) ₂ , C (O ) N (aryl) _2, C (O) N _{(heteroaryl) 2, SO 2 NH 2,} SO 2 NH- alkyl, SO ₂ NH- aryl, SO ₂ NH- heteroaryl, SO ₂ NH- alkyl - aryl, SO ₃ H, SO ₂ O- alkyl, SO ₂ O-aryl, SO ₂ O-alkyl - aryl, alkyl, cycloalkyl, heterocyclyl, alkyl - cycloalkyl, alkyl - heterocyclyl, alkyl - aryl, alkyl - heteroaryl, aryl Or the above-mentioned alkyl substituents, cycloalkyl, which may be substituted with heteroaryl, and relating to those moieties Substituent, heterocyclyl substituents include alkyl - heterocyclyl substituents include alkyl - aryl substituent, an alkyl - cycloalkyl substituent, an alkyl - heteroaryl substituent, an aryl substituent and heteroaryl substituents may be further substituted,
And R2 is
(I) unsubstituted or substituted butyl -aryl,
The butyl - aryl groups, one or more identical or different F, Cl, Br, I, CF 3, CN, NH 2, NH- alkyl, NH- cycloalkyl, NH- heterocyclyl, NH- aryl, NH -Heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, N (alkyl) ₂ , NHC (O) -alkyl, NHC (O) -cycloalkyl , NHC (O) -heterocyclyl, NHC (O) -aryl, NHC (O) -heteroaryl, NHC (O) -alkyl-aryl, NHC (O) -alkyl-heteroaryl, NHSO ₂ -alkyl, NHSO ₂ — cycloalkyl, NHSO ₂ - heterocyclyl, NHSO ₂ - aryl, NHS ₂ - heteroaryl, NHSO ₂ - alkyl - aryl, NHSO ₂ - alkyl - heteroaryl, NO _2, SH, S- alkyl, S- cycloalkyl, S- heterocyclyl, S- aryl, S- heteroaryl, = O, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl, O-alkyl- Heteroaryl, OC (O) -alkyl, OC (O) -cycloalkyl, OC (O) -heterocyclyl, OC (O) -aryl, OC (O) -heteroaryl, OC (O) -alkyl-aryl, OC (O) - alkyl - heteroaryl, OSO ₃ H, OSO ₂ - alkyl, OSO ₂ - Shikuroa Kill, OSO ₂ - heterocyclyl, OSO ₂ - aryl, OSO ₂ - heteroaryl, OSO ₂ - alkyl - aryl, OSO ₂ - alkyl - heteroaryl, OP (O) (OH) 2, C (O) - alkyl, C (O) - aryl, C (O) - heteroaryl, CO ₂ H, CO ₂ - alkyl, CO ₂ - cycloalkyl, CO ₂ - heterocyclyl, CO ₂ - aryl, CO ₂ - heteroaryl, CO ₂ - alkyl - cycloalkyl, CO ₂ - alkyl - heterocyclyl, CO ₂ - alkyl - aryl, CO ₂ - alkyl - _{heteroaryl, C (O) -NH 2,} C (O) NH- alkyl, C (O) NH- cycloalkyl, C (O) NH-heterocyclyl, C (O) NH-aryl, C (O) NH-heteroaryl, C (O) NH-alkyl-cyclo Alkyl, C (O) NH-alkyl-heterocyclyl, C (O) NH-alkyl-aryl, C (O) NH-alkyl-heteroaryl, C (O) N (alkyl) ₂ , C (O) N (cyclo _{alkyl) 2, C (O) N} ( _{aryl) 2, C (O) N} ( heteroaryl) _2, SO- alkyl, SO- aryl, SO ₂ - alkyl, SO ₂ - aryl, SO ₂ NH _2, SO ₂ NH- alkyl, SO ₂ NH- aryl, SO ₂ NH- heteroaryl, SO ₂ NH- alkyl - aryl, SO ₃ H, SO ₂ O- alkyl, SO ₂ O-aryl, SO ₂ O-alkyl - aryl, alkyl , Substituted with cycloalkyl, heterocyclyl, aryl or heteroaryl,
(II) unsubstituted or substituted butyl -heteroaryl,
The butyl - heteroaryl group, one or more identical or different F, Cl, Br, I, CF 3, CN, NH 2, NH- alkyl, NH- cycloalkyl, NH- heterocyclyl, NH- aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, N (alkyl) ₂ , NHC (O) -alkyl, NHC (O) -cyclo Alkyl, NHC (O) -heterocyclyl, NHC (O) -aryl, NHC (O) -heteroaryl, NHC (O) -alkyl-aryl, NHC (O) -alkyl-heteroaryl, NHSO ₂ -alkyl, NHSO ₂ - cycloalkyl, NHSO ₂ - heterocyclyl, NHSO ₂ - aryl, HSO ₂ - heteroaryl, NHSO ₂ - alkyl - aryl, NHSO ₂ - alkyl - heteroaryl, NO _2, SH, S- alkyl, S- cycloalkyl, S- heterocyclyl, S- aryl, S- heteroaryl, OH, OCF _3, O- alkyl, O- cycloalkyl, O- heterocyclyl, O- aryl, O- heteroaryl, O- alkyl - cycloalkyl, O- alkyl - heterocyclyl, O- alkyl - aryl, O- alkyl - heteroaryl OC (O) -alkyl, OC (O) -cycloalkyl, OC (O) -heterocyclyl, OC (O) -aryl, OC (O) -heteroaryl, OC (O) -alkyl-aryl, OC (O ) - alkyl - heteroaryl, OSO ₃ H, OSO ₂ - alkyl, OSO ₂ - Shikuroa Kill, OSO ₂ - heterocyclyl, OSO ₂ - aryl, OSO ₂ - heteroaryl, OSO ₂ - alkyl - aryl, OSO ₂ - alkyl - heteroaryl, OP (O) (OH) 2, C (O) - alkyl, C (O) - aryl, C (O) - heteroaryl, CO ₂ H, CO ₂ - alkyl, CO ₂ - cycloalkyl, CO ₂ - heterocyclyl, CO ₂ - aryl, CO ₂ - heteroaryl, CO ₂ - alkyl - cycloalkyl, CO ₂ - alkyl - heterocyclyl, CO ₂ - alkyl - aryl, CO ₂ - alkyl - _{heteroaryl, C (O) -NH 2,} C (O) NH- alkyl, C (O) NH- cycloalkyl, C (O) NH-heterocyclyl, C (O) NH-aryl, C (O) NH-heteroaryl, C (O) NH-alkyl-cyclo Alkyl, C (O) NH-alkyl-heterocyclyl, C (O) NH-alkyl-aryl, C (O) NH-alkyl-heteroaryl, C (O) N (alkyl) ₂ , C (O) N (cyclo _{alkyl) 2, C (O) N} ( _{aryl) 2, C (O) N} ( heteroaryl) _2, SO- alkyl, SO- aryl, SO ₂ - alkyl, SO ₂ - aryl, SO ₂ NH _2, SO ₂ NH- alkyl, SO ₂ NH- aryl, SO ₂ NH- heteroaryl, SO ₂ NH- alkyl - aryl, SO ₃ H, SO ₂ O- alkyl, SO ₂ O-aryl, SO ₂ O-alkyl - aryl, alkyl , Substituted with cycloalkyl, heterocyclyl, aryl or heteroaryl,
Or a mixture of these enantiomers and / or diastereomers, in their racemic form, in their pure enantiomers and / or diastereomers, or in a mixture of these enantiomers and / or diastereomers For treatment or prevention of physiological and / or pathophysiological conditions mediated by the ras-Raf-Mek-Erk signaling pathway in mammals in the form of Use for the manufacture of a medicament, wherein said physiological and / or pathophysiological state is "malignant tumor, benign tumor, inflammatory disease, inflammation, pain, rheumatic disease, arthritic disease, HIV Infection, neurological or neurodegenerative disease, rheumatism, arthritis, AIDS, ARC (AIDS related syndrome), Kaposi's sarcoma, brain and / or nervous system And / or tumors derived from meninges, dementia, Alzheimer's disease, hyperproliferative disease, psoriasis, endometriosis, scarring, benign prostatic hypertrophy (BPH), immune system disease, autoimmune disease, immunodeficiency disease, colon tumor, stomach tumor, intestinal tumor, lung tumor, pancreatic tumor, before prostate tumor, leukemia, melanoma, liver tumors, kidney tumor, head tumor, pharynx tumor, glioma, breast tumors, uterine cancer, intrauterine Membrane cancer, uterine vaginal carcinoma, brain tumor, adenocarcinoma, bladder cancer, stomach tumor, colorectal tumor, esophageal cancer, gynecological tumor, ovarian tumor, thyroid cancer, lymphoma, chronic leukemia, acute leukemia, restenosis, diabetes, Diabetic nephropathy, fibrosis, cystic fibrosis, malignant nephrosclerosis, thrombotic microvascular syndrome, organ transplant rejection, glomerulopathy, metabolic disease, solid / fixed tumor, rheumatoid arthritis, diabetic retinopathy , Asthma, allergies, allergic diseases Chronic obstructive pulmonary disease, inflammatory bowel disease, fibrosis, atherosclerosis, heart disease, cardiovascular disease, myocardial disease, vascular disease, angiogenic disease, kidney disease, rhinitis, Graves' disease, local Ischemia, heart failure, ischemia, cardiac hypertrophy, renal failure, cardiomyocyte dysfunction, hypertension, vasoconstriction, stroke, anaphylactic shock, platelet aggregation, skeletal muscle atrophy, obesity, overweight, glucose homeostasis, congestive heart failure Said use selected from the group consisting of: angina pectoris, heart attack, myocardial infarction, hyperglycemia, hypoglycemia, hypertension. The use according to claim 1, wherein the alkyl group is methyl, ethyl, n-propyl, 2-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n. - hexyl, 2-hexyl, n- octyl, Echirueniru (vinyl), ethynyl, propenyl _{(-CH 2 CH = CH 2;} -CH = CH-CH 3, -C (= CH 2) -CH 3), propynyl ( _{-CH 2 -C≡CH, -C≡C-CH 3} ), butenyl, butynyl, pentenyl, pentynyl, hexenyl, hexynyl, heptenyl, heptynyl the use, octenyl, is selected from the group consisting octynyl.   3. Use according to claim 1 or 2, wherein the heterocyclyl group is selected from the group consisting of tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl.   Use according to any one of claims 1 to 3, wherein the heteroaryl group is pyrrolyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, Said use selected from the group consisting of phthalazinyl, indolyl, indazolyl, indolizinyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl, acridinyl. Use according to any one of claims 1 to 4, wherein the compound is
Compound 90:
1- [3- (4- {2- [2- (2-hydroxy-ethoxy) -ethoxy] -ethoxy} -phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4 -Phenyl-butyl) -urea

Compound 91:
1- [3- (3,5-Dimethyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 92:
1- (4-Phenyl-butyl) -3- [3- (2,3,4-trimethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -urea

Compound 94:
1- [3- (3H-Benzimidazol-5-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 95:
1- [3- (3-Amino-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 97:
1- [3- (1-Methyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-p-tolyl-butyl) -urea

Compound 98:
1- [3- (3,4-Dimethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea

Compound 99:
1- [4- (4-Fluoro-phenyl) -butyl] -3- [3- (1-methyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl]- urea

Compound 100:
1- (4-Methyl-4-phenyl-pentyl) -3- [3- (1-propyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -urea

Compound 101:
1- [3- (2,4-Dimethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 102:
1- [3- (2-Ethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 103:
1- [3- (3,5-Dichloro-4-hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 104:
1- [3- (3-Hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 105:
1- (4-Phenyl-butyl) -3- [3- (2H-pyrazol-3-yl) -pyrido [2,3-b] pyrazin-6-yl] -urea

Compound 106:
1- [3- (4-Hydroxy-2-methyl-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 107:
Acetic acid 4- {6- [3- (4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -phenyl ester

Compound 108:
1- [3- (1-Ethyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 109:
1- [3- (3-Bromo-4-hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 110:
1- (4-Phenyl-butyl) -3- (3-pyridin-3-yl-pyrido [2,3-b] pyrazin-6-yl) -urea

Compound 111:
1- [3- (1-Methyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (1,2,3,4-tetrahydro-naphthalene-2 -Ylmethyl) -urea

Compound 112:
1- [3- (2,3-Dimethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea

Compound 113:
1- [3- (5-Methyl-1-phenyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 114:
1- [3- (1-Butyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 115:
1- [4- (4-Methoxy-phenyl) -butyl] -3- [3- (1-methyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl]- urea

Compound 118:
1- [3- (4-Methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 120:
1- (4-Phenyl-butyl) -3- (3-o-tolyl-pyrido [2,3-b] pyrazin-6-yl) -urea

Compound 121:
3- {6- [3- (4-Phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -benzoic acid ethyl ester

Compound 122:
Ethyl-carbamic acid 4- {6- [3- (4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -phenyl ester

Compound 123:
1- [3- (4-Amino-3-methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 124:
1- [3- (2-Methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 125:
1-((R) -1-methyl-4-phenyl-butyl) -3- [3- (2,3,4-trimethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl]- urea

Compound 126:
1- (1-Methyl-4-phenyl-butyl) -3- [3- (1-propyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -urea

Compound 127:
1- {3- [1- (2-morpholin-4-yl-ethyl) -1H-pyrazol-4-yl] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl) -Butyl) -urea

Compound 128:
1- [3- (2-Ethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea

Compound 129:
1- [3- (3-Chloro-4-hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl)- urea

Compound 130:
1- [3- (2-Amino-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 131:
1- (4-Oxo-4-phenyl-butyl) -3- [3- (1-propyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -urea

Compound 132:
Carbonic acid ethyl ester 4- {6- [3- (4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -phenyl ester

Compound 133:
1- [3- (2-hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 135:
2,2-Dimethyl-propionic acid 4- {6- [3- (4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -phenyl ester

Compound 137:
1- [3- (4-Methylsulfanyl-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 138:
1- [3- (3-Cyano-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 144:
1- [3- (4-Fluoro-2-hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 145:
1- {3- [4-Methoxy-3- (morpholine-4-sulfonyl) -phenyl] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl-butyl) -urea

Compound 146:
1- [3- (2-Methoxy-pyridin-3-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 147:
1- [3- (4-Hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea

Compound 148:
1- [3- (3-Hydroxy-4-methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl)- urea

Compound 149:
1- (3-furan-3-yl-pyrido [2,3-b] pyrazin-6-yl) -3-((R) -1-methyl-4-phenyl-butyl) -urea

Compound 150:
1-((R) -1-methyl-4-phenyl-butyl) -3- (3-pyridin-3-yl-pyrido [2,3-b] pyrazin-6-yl) -urea

Compound 151:
1- [3- (3-Hydroxy-4-methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 152:
1- (3-furan-3-yl-pyrido [2,3-b] pyrazin-6-yl) -3- (4-phenyl-butyl) -urea

Compound 155:
1- [3- (1-Methyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 156:
1- [3- (4-Hydroxymethyl-2-methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -Urea

Compound 157:
1-((R) -1-methyl-4-phenyl-butyl) -3- (3-pyridin-4-yl-pyrido [2,3-b] pyrazin-6-yl) -urea

Compound 158:
1- [3- (3-Hydroxymethyl-2-methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -Urea

Compound 159:
1- (4-Phenyl-butyl) -3- [3- (1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -urea

Compound 160:
1- [3- (4-Hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 161:
1- [3- (2-Methoxy-pyridin-3-yl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl)- urea

Compound 162:
1- {3- [1- (3-hydroxy-propyl) -1H-pyrazol-4-yl] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl-butyl)- urea

Compound 163:
1- {3- [1- (2,2-difluoro-ethyl) -1H-pyrrol-3-yl] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl-butyl ) -Urea

Compound 164:
1- (1-Methyl-4-phenyl-butyl) -3- [3- (1-methyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -urea

Compound 165:
Phosphoric acid mono- (4- {6- [3- (4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -phenyl) ester

Compound 167:
1- [3- (4-Hydroxymethyl-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea

Compound 168:
1-((R) -1-methyl-4-phenyl-butyl) -3- {3- [1- (2-morpholin-4-yl-ethyl) -1H-pyrazol-4-yl] -pyrido [2 , 3-b] pyrazin-6-yl} -urea

Compound 169:
1- (4-Methyl-4-phenyl-pentyl) -3- [3- (1-methyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -urea

Compound 170:
1-((R) -1-methyl-4-phenyl-butyl) -3- [3- (1-propyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl ] -Urea

Compound 171:
1-((R) -1-methyl-4-phenyl-butyl) -3- [3- (1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -urea

Compound 174:
1- [3- (3-Fluoro-4-hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 175:
1- [3- (3-Hydroxymethyl-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 177:
1- [3- (3,5-Dimethyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl -Butyl) -urea

Compound 178:
1- [3- (3,4-Dimethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 179:
1- [3- (2-Methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea

Compound 180:
1-((R) -1-methyl-4-phenyl-butyl) -3- [3- (1-methyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl ] -Urea

Compound 181:
1- [3- (3-Hydroxymethyl-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea

Compound 182:
1- [3- (4-Hydroxymethyl-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 183:
1- [3- (2,4-Dimethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea

Compound 184:
1- (4-Phenyl-butyl) -3- (3-pyridin-4-yl-pyrido [2,3-b] pyrazin-6-yl) -urea

Compound 185:
1- [3- (3-Fluoro-4-hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl)- urea

Compound 186:
1- [3- (3-Chloro-4-hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 188:
1- [3- (4- {2- [2- (2-hydroxy-ethoxy) -ethoxy] -ethoxy} -phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-(( R) -1-Methyl-4-phenyl-butyl) -urea

Compound 189:
1- {3- [1- (2-hydroxy-ethyl) -1H-pyrazol-4-yl] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl-butyl)- urea

Compound 194:
2-Methoxy-4- {6- [3- (4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -benzoic acid

Compound 195:
(S) -2-Amino-3- (4- {6- [3-((R) -1-methyl-4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazine-3- Yl} -phenyl) -propionic acid; hydrochloride

Compound 196:
3- {6- [3-((R) -1-methyl-4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -benzoic acid

Compound 197:
(S) -2-Amino-3- (4- {6- [3- (4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -phenyl) -propionic acid

Compound 198:
3- {6- [3- (4-Phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -benzoic acid

Compound 199:
1- {3- [4- (2-methoxy-ethoxy) -phenyl] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl-butyl) -urea

Compound 200:
rac 1- {3- [4- (2-hydroxy-propoxy) -phenyl] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl-butyl) -urea

Compound 201:
1- (3- {4- [2- (2-hydroxy-ethoxy) -ethoxy] -phenyl} -pyrido [2,3-b] pyrazin-6-yl) -3- (4-phenyl-butyl)- urea

Compound 202:
1- {3- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl-butyl) -urea

Compound 203:
1- [3- (3-Methoxymethyl-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea

Compound 204:
1- {3- [3- (2-methoxy-ethoxymethyl) -phenyl] -pyrido [2,3-b] pyrazin-6-yl} -3-((R) -1-methyl-4-phenyl- Butyl) -urea

Compound 205:
1- {3- [3- (2-Dimethylamino-ethoxymethyl) -phenyl] -pyrido [2,3-b] pyrazin-6-yl} -3-((R) -1-methyl-4-phenyl -Butyl) -urea

Compound 206:
Methanesulfonic acid 3- {6- [3-((R) -1-methyl-4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -benzyl ester

Compound 207:
1-((R) -1-methyl-4-phenyl-butyl) -3- {3- [3- (2-morpholin-4-yl-ethoxymethyl) -phenyl] -pyrido [2,3-b] Pyrazin-6-yl} -urea

Compound 208:
Ethyl-carbamic acid 3- {6- [3-((R) -1-methyl-4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -benzyl ester

Compound 209:
1-((R) -1-methyl-4-phenyl-butyl) -3- {3- [3-((2R, 3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- Hydroxymethyl-tetrahydro-pyran-2-yloxymethyl) -phenyl] -pyrido [2,3-b] pyrazin-6-yl} -urea

Said use selected from the group consisting of:   6. Use according to any one of claims 1 to 5, wherein the treatment or prevention is effected by modulation of the ras-Raf-Mek-Erk signaling pathway.   7. Use according to any one of claims 1 to 6, wherein the regulation of the ras-Raf-Mek-Erk signaling pathway is tyrosine kinase, serine / threonine kinase, receptor tyrosine kinase, cytoplasmic tyrosine kinase, Said use made by modulation of one or more enzymes selected from the group consisting of cytoplasmic serine / threonine kinases.   8. The use according to claim 7, wherein the enzyme is selected from the group consisting of Erk, Erk1, Erk2.   9. Use according to any one of claims 1 to 8, wherein one or more enzymes are regulated.   10. Use according to any one of claims 1 to 9, wherein the modulation is inhibition.   Use according to any one of claims 1 to 5, wherein the compounds 90, 91, 92, 94, 95, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 118, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 135, 137, 138, 144, 145, 146, 147, 148, 149, 150, 151, 152, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 167, 168, 169, 170, 171, 174, 175, 177, 178, 179, 180, 181, 182, 183, 184, 185 At least one compound selected from the group consisting of 186, 188, 189, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208 and 209 The ras-Raf-Mek-Erk signaling pathway or its enzyme can be regulated or inhibited with high selectivity and can have these effects, and the above-mentioned multiple mechanisms of action and therapeutic approaches Said use which can be used in this signaling pathway or enzyme.   12. Use according to any one of claims 1 to 11, wherein the medicament comprises at least one further pharmacologically active substance.   12. Use according to any one of claims 1 to 11, wherein the medicament is administered before and / or during and / or after treatment with radiation therapy and / or surgery.   13. Use according to claim 12, wherein said further pharmacologically effective substance is a DNA topoisomerase I and / or II inhibitor, a DNA intercalator, an alkylating agent, a microtubule destabilizing factor, a hormone and Selected from the group consisting of “and / or growth factor receptor agonists and / or antagonists, antibodies to growth factors and their receptors, kinase inhibitors, alkylphospholipids, antimetabolites” Substances are asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, cholaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycin), epirubicin, etoposide 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifene, streptozocin, tamoxifen Thioguanine, topotecan, vinblastine, vincristine, vindesine, aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine, cladribine, busulfan, diethylstilbestrol, 2 ', 2'-difluorodeoxycytidine, docetaxel, erythrohydroxynonyladenine , Ethinyl estradiol, 5-fluorodeoxyuridine, 5- Luodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, oxaliplatin, pentostatin, N-phosphonoacetyl-L-aspartate (PALA), pricamycin, semstin, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, vinorelbine, epothilone, gemcitabine, taxotere, BCNU, CCNU, DTIC, 5-fluorouracil, Herceptin, Avastin, Erbitux, Sorafenib, Gleevec, Iressa, Tarceva, Rapamycin, Perifosine Miltefosine the use, edelfosine, is selected from the group consisting of actinomycin D. Compound 90:
1- [3- (4- {2- [2- (2-hydroxy-ethoxy) -ethoxy] -ethoxy} -phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4 -Phenyl-butyl) -urea
Compound 91:
1- [3- (3,5-Dimethyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea
Compound 92:
1- (4-Phenyl-butyl) -3- [3- (2,3,4-trimethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -urea
Compound 94:
1- [3- (3H-Benzimidazol-5-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea
Compound 95:
1- [3- (3-Amino-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea
Compound 97:
1- [3- (1-Methyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-p-tolyl-butyl) -urea
Compound 98:
1- [3- (3,4-Dimethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea
Compound 99:
1- [4- (4-Fluoro-phenyl) -butyl] -3- [3- (1-methyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl]- urea
Compound 100:
1- (4-Methyl-4-phenyl-pentyl) -3- [3- (1-propyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -urea
Compound 101:
1- [3- (2,4-Dimethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea
Compound 102:
1- [3- (2-Ethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea
Compound 103:
1- [3- (3,5-Dichloro-4-hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea
Compound 104:
1- [3- (3-Hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea
Compound 105:
1- (4-Phenyl-butyl) -3- [3- (2H-pyrazol-3-yl) -pyrido [2,3-b] pyrazin-6-yl] -urea
Compound 106:
1- [3- (4-Hydroxy-2-methyl-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea
Compound 107:
Acetic acid 4- {6- [3- (4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -phenyl ester
Compound 108:
1- [3- (1-Ethyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea
Compound 109:
1- [3- (3-Bromo-4-hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea
Compound 110:
1- (4-Phenyl-butyl) -3- (3-pyridin-3-yl-pyrido [2,3-b] pyrazin-6-yl) -urea
Compound 111:
1- [3- (1-Methyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (1,2,3,4-tetrahydro-naphthalene-2 -Ylmethyl) -urea
Compound 112:
1- [3- (2,3-Dimethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea
Compound 113:
1- [3- (5-Methyl-1-phenyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea
Compound 114:
1- [3- (1-Butyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea
Compound 115:
1- [4- (4-Methoxy-phenyl) -butyl] -3- [3- (1-methyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl]- urea
Compound 118:
1- [3- (4-Methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea
Compound 120:
1- (4-Phenyl-butyl) -3- (3-o-tolyl-pyrido [2,3-b] pyrazin-6-yl) -urea
Compound 121:
3- {6- [3- (4-Phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -benzoic acid ethyl ester
Compound 122:
Ethyl-carbamic acid 4- {6- [3- (4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -phenyl ester
Compound 123:
1- [3- (4-Amino-3-methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea
Compound 124:
1- [3- (2-Methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea
Compound 125:
1-((R) -1-methyl-4-phenyl-butyl) -3- [3- (2,3,4-trimethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl]- urea
Compound 126:
1- (1-Methyl-4-phenyl-butyl) -3- [3- (1-propyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -urea
Compound 127:
1- {3- [1- (2-morpholin-4-yl-ethyl) -1H-pyrazol-4-yl] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl) -Butyl) -urea
Compound 128:
1- [3- (2-Ethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea
Compound 129:
1- [3- (3-Chloro-4-hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl)- urea
Compound 130:
1- [3- (2-Amino-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea
Compound 131:
1- (4-Oxo-4-phenyl-butyl) -3- [3- (1-propyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -urea
Compound 132:
Carbonic acid ethyl ester 4- {6- [3- (4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -phenyl ester
Compound 133:
1- [3- (2-hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea
Compound 135:
2,2-Dimethyl-propionic acid 4- {6- [3- (4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -phenyl ester
Compound 137:
1- [3- (4-Methylsulfanyl-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea
Compound 138:
1- [3- (3-Cyano-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea
Compound 144:
1- [3- (4-Fluoro-2-hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea
Compound 145:
1- {3- [4-Methoxy-3- (morpholine-4-sulfonyl) -phenyl] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl-butyl) -urea
Compound 146:
1- [3- (2-Methoxy-pyridin-3-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea
Compound 147:
1- [3- (4-Hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea
Compound 148:
1- [3- (3-Hydroxy-4-methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl)- urea
Compound 149:
1- (3-furan-3-yl-pyrido [2,3-b] pyrazin-6-yl) -3-((R) -1-methyl-4-phenyl-butyl) -urea
Compound 150:
1-((R) -1-methyl-4-phenyl-butyl) -3- (3-pyridin-3-yl-pyrido [2,3-b] pyrazin-6-yl) -urea
Compound 151:
1- [3- (3-Hydroxy-4-methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea
Compound 152:
1- (3-furan-3-yl-pyrido [2,3-b] pyrazin-6-yl) -3- (4-phenyl-butyl) -urea
Compound 155:
1- [3- (1-Methyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea
Compound 156:
1- [3- (4-Hydroxymethyl-2-methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -Urea
Compound 157:
1-((R) -1-methyl-4-phenyl-butyl) -3- (3-pyridin-4-yl-pyrido [2,3-b] pyrazin-6-yl) -urea
Compound 158:
1- [3- (3-Hydroxymethyl-2-methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -Urea
Compound 159:
1- (4-Phenyl-butyl) -3- [3- (1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -urea
Compound 160:
1- [3- (4-Hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea
Compound 161:
1- [3- (2-Methoxy-pyridin-3-yl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl)- urea
Compound 162:
1- {3- [1- (3-hydroxy-propyl) -1H-pyrazol-4-yl] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl-butyl)- urea
Compound 163:
1- {3- [1- (2,2-difluoro-ethyl) -1H-pyrrol-3-yl] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl-butyl ) -Urea
Compound 164:
1- (1-Methyl-4-phenyl-butyl) -3- [3- (1-methyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -urea
Compound 165:
Phosphoric acid mono- (4- {6- [3- (4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -phenyl) ester
Compound 167:
1- [3- (4-Hydroxymethyl-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea
Compound 168:
1-((R) -1-methyl-4-phenyl-butyl) -3- {3- [1- (2-morpholin-4-yl-ethyl) -1H-pyrazol-4-yl] -pyrido [2 , 3-b] pyrazin-6-yl} -urea
Compound 169:
1- (4-Methyl-4-phenyl-pentyl) -3- [3- (1-methyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -urea
Compound 170:
1-((R) -1-methyl-4-phenyl-butyl) -3- [3- (1-propyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl ] -Urea
Compound 171:
1-((R) -1-methyl-4-phenyl-butyl) -3- [3- (1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -urea
Compound 174:
1- [3- (3-Fluoro-4-hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea
Compound 175:
1- [3- (3-Hydroxymethyl-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea
Compound 177:
1- [3- (3,5-Dimethyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl -Butyl) -urea
Compound 178:
1- [3- (3,4-Dimethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea
Compound 179:
1- [3- (2-Methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea
Compound 180:
1-((R) -1-methyl-4-phenyl-butyl) -3- [3- (1-methyl-1H-pyrazol-4-yl) -pyrido [2,3-b] pyrazin-6-yl ] -Urea
Compound 181:
1- [3- (3-Hydroxymethyl-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea
Compound 182:
1- [3- (4-Hydroxymethyl-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea
Compound 183:
1- [3- (2,4-Dimethoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea
Compound 184:
1- (4-Phenyl-butyl) -3- (3-pyridin-4-yl-pyrido [2,3-b] pyrazin-6-yl) -urea
Compound 185:
1- [3- (3-Fluoro-4-hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl)- urea
Compound 186:
1- [3- (3-Chloro-4-hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea
Compound 188:
1- [3- (4- {2- [2- (2-hydroxy-ethoxy) -ethoxy] -ethoxy} -phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-(( R) -1-Methyl-4-phenyl-butyl) -urea
Compound 189:
1- {3- [1- (2-hydroxy-ethyl) -1H-pyrazol-4-yl] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl-butyl)- urea
Compound 194:
2-Methoxy-4- {6- [3- (4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -benzoic acid
Compound 195:
(S) -2-Amino-3- (4- {6- [3-((R) -1-methyl-4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazine-3- Yl} -phenyl) -propionic acid; hydrochloride
Compound 196:
3- {6- [3-((R) -1-methyl-4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -benzoic acid
Compound 197:
(S) -2-Amino-3- (4- {6- [3- (4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -phenyl) -propionic acid
Compound 198:
3- {6- [3- (4-Phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -benzoic acid
Compound 199:
1- {3- [4- (2-methoxy-ethoxy) -phenyl] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl-butyl) -urea
Compound 200:
rac 1- {3- [4- (2-hydroxy-propoxy) -phenyl] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl-butyl) -urea
Compound 201:
1- (3- {4- [2- (2-hydroxy-ethoxy) -ethoxy] -phenyl} -pyrido [2,3-b] pyrazin-6-yl) -3- (4-phenyl-butyl)- urea
Compound 202:
1- {3- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl-butyl) -urea
Compound 203:
1- [3- (3-Methoxymethyl-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl-butyl) -urea
Compound 204:
1- {3- [3- (2-methoxy-ethoxymethyl) -phenyl] -pyrido [2,3-b] pyrazin-6-yl} -3-((R) -1-methyl-4-phenyl- Butyl) -urea
Compound 205:
1- {3- [3- (2-Dimethylamino-ethoxymethyl) -phenyl] -pyrido [2,3-b] pyrazin-6-yl} -3-((R) -1-methyl-4-phenyl -Butyl) -urea
Compound 206:
Methanesulfonic acid 3- {6- [3-((R) -1-methyl-4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -benzyl ester
Compound 207:
1-((R) -1-methyl-4-phenyl-butyl) -3- {3- [3- (2-morpholin-4-yl-ethoxymethyl) -phenyl] -pyrido [2,3-b] Pyrazin-6-yl} -urea
Compound 208:
Ethyl-carbamic acid 3- {6- [3-((R) -1-methyl-4-phenyl-butyl) -ureido] -pyrido [2,3-b] pyrazin-3-yl} -benzyl ester and
Compound 209:
1-((R) -1-methyl-4-phenyl-butyl) -3- {3- [3-((2R, 3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- Pyridopyrazine selected from the group consisting of hydroxymethyl-tetrahydro-pyran-2-yloxymethyl) -phenyl] -pyrido [2,3-b] pyrazin-6-yl} -urea, physiologically Tolerable salts, their racemic forms, their pure enantiomers and / or diastereomers, or mixtures of these enantiomers and / or diastereomers, or tautomers thereof. 1 or selected from the group consisting of the PI3K-Akt signaling pathway and / or the ras-Raf-Mek-Erk signaling pathway, comprising a pharmacologically effective amount of at least one compound according to claim 15. A pharmaceutical composition for the treatment or prevention of a physiological and / or pathophysiological condition that can be treated by modulation of a plurality of signaling pathways, wherein said physiological and / or pathophysiological condition comprises: “Malignant tumor, benign tumor, inflammatory disease, inflammation, pain, rheumatic disease, arthritic disease, HIV infection, neurological or neurodegenerative disease, rheumatoid arthritis, AIDS, ARC (AIDS related syndrome), Kaposi sarcoma, brain And / or tumors derived from the nervous system and / or meninges, dementia, Alzheimer's disease, hyperproliferative disease, psoriasis, endometriosis, scarring, benign prognosis Hypertrophy (BPH), immune system disorders, autoimmune diseases, immunodeficiency diseases, colon tumor, stomach tumor, intestine tumor, lung tumor, pancreatic tumor, before prostate tumor, leukemia, melanoma, liver tumor, kidney tumor, head Tumor, pharyngeal tumor, glioma, breast tumor, uterine cancer, endometrial cancer, uterine vaginal carcinoma, brain tumor, adenocarcinoma, bladder cancer, gastric tumor, colorectal tumor, esophageal cancer, gynecological tumor, ovary Tumor, thyroid cancer, lymphoma, chronic leukemia, acute leukemia, restenosis, diabetes, diabetic nephropathy, fibrosis, cystic fibrosis, malignant nephrosclerosis, thrombotic microvascular syndrome, organ transplant rejection, glomerulopathy, Metabolic disease, solid / fixed tumor, rheumatoid arthritis, diabetic retinopathy, asthma, allergy, allergic disease, chronic obstructive pulmonary disease, inflammatory bowel disease, fibrosis, atherosclerosis, heart disease, Cardiovascular disease, myocardial disease, vascular disease , Angiogenic disease, kidney disease, rhinitis, Graves' disease, local ischemia, heart failure, ischemia, cardiac hypertrophy, renal failure, cardiomyocyte dysfunction, hypertension, vasoconstriction, stroke attack, anaphylactic shock, platelet aggregation reaction , Skeletal muscle atrophy, obesity, overweight, glucose homeostasis, congestive heart failure, angina pectoris, heart attack, myocardial infarction, hyperglycemia, hypoglycemia, hypertension.   16. A pharmaceutical composition comprising a pharmacologically effective amount of at least one compound according to claim 15.   18. A pharmaceutical composition according to claim 17, wherein the active substance is present in a unit dose of 0.001 mg to 100 mg per kg body weight of the patient.   19. A pharmaceutical composition according to claim 17 or 18, wherein the composition further comprises at least one pharmaceutically acceptable excipient and / or adjuvant.   20. The pharmaceutical composition according to any one of claims 17 to 19, wherein the composition contains at least one further pharmacologically active substance.   21. The pharmaceutical composition according to claim 20, wherein said further pharmacologically effective substance is "DNA topoisomerase I and / or II inhibitor, DNA intercalator, alkylating agent, microtubule destabilizing factor" Selected from the group consisting of hormones and / or growth factor receptor agonists and / or antagonists, antibodies to growth factors and their receptors, kinase inhibitors, alkylphospholipids, antimetabolites, Bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, cholaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycin), epirubicin, etoposide, 5-fluorou Sil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechloretamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifene, streptozocin, tamoxifen, thioxifine Topotecan, vinblastine, vincristine, vindesine, aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine, cladribine, busulfan, diethylstilbestrol, 2 ', 2'-difluorodeoxycytidine, docetaxel, erythrohydroxynonyladenine, ethynyl Estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxy Lysine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, oxaliplatin, pentostatin, N-phospho Noacetyl-L-aspartate (PALA), pricamycin, semstin, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, vinorelbine, epothilone, gemcitabine, taxotere, BCNU, CCNU, DTIC, 5-fluorouracil, Herceptin, Avastin , Erbitux, Sorafenib, Gleevec, Iressa, Tarceva, Rapamycin, Perifosine, Miltefosine Edelfosine, said pharmaceutical composition is selected from the group consisting of actinomycin D ".   A pharmacologically effective amount of at least one compound according to claim 15 and a drug of at least one further pharmacologically effective substance according to any one of claims 20 to 21. A kit comprising a physically effective amount. Compound 93:
1- [3- (4-Methyl-piperazin-1-yl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 96:
1- (4-Phenyl-butyl) -3- (3-piperazin-1-yl-pyrido [2,3-b] pyrazin-6-yl) -urea; hydrochloride

Compound 116:
1- (4-Phenyl-butyl) -3- [3- (piperidin-4-ylamino) -pyrido [2,3-b] pyrazin-6-yl] -urea

Compound 117:
1- (4-Phenyl-butyl) -3- {3-[(pyridin-4-ylmethyl) -amino] -pyrido [2,3-b] pyrazin-6-yl} -urea

Compound 119:
1- (4-Phenyl-butyl) -3- (3-propylamino-pyrido [2,3-b] pyrazin-6-yl) -urea

Compound 134:
1- [3- (4-Hydroxy-cyclohexylamino) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 139:
1- (4-Phenyl-butyl) -3- [3- (3,4,5-trimethoxy-phenylamino) -pyrido [2,3-b] pyrazin-6-yl] -urea

Compound 140:
1- {3-[(S) -1- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl- Butyl) -urea

Compound 141:
1- [3- (3-Hydroxy-4,5-dimethoxy-phenylamino) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-phenyl-butyl) -urea

Compound 142:
1- {3- [1- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -pyrido [2,3-b] pyrazin-6-yl} -3- (4-phenyl-butyl) -urea

Compound 153:
1-((R) -1-methyl-4-phenyl-butyl) -3- [3- (4-methyl-piperazin-1-yl) -pyrido [2,3-b] pyrazin-6-yl]- urea

Compound 154:
1-((R) -1-methyl-4-phenyl-butyl) -3- (3-piperidin-1-yl-pyrido [2,3-b] pyrazin-6-yl) -urea

Compound 166:
1-((R) -1-methyl-4-phenyl-butyl) -3- (3-morpholin-4-yl-pyrido [2,3-b] pyrazin-6-yl) -urea

Compound 172:
1- (4-Phenyl-butyl) -3- (3-pyrrolidin-1-yl-pyrido [2,3-b] pyrazin-6-yl) -urea

Compound 173:
1-((R) -1-methyl-4-phenyl-butyl) -3- (3-pyrrolidin-1-yl-pyrido [2,3-b] pyrazin-6-yl) -urea

Compound 176:
1- (3-morpholin-4-yl-pyrido [2,3-b] pyrazin-6-yl) -3- (4-phenyl-butyl) -urea

Compound 187:
1- [3-((S) -3-Methyl-morpholin-4-yl) -pyrido [2,3-b] pyrazin-6-yl] -3-((R) -1-methyl-4-phenyl -Butyl) -urea

For the manufacture of a medicament for the treatment or prevention of a physiological and / or pathophysiological condition mediated by the ras-Raf-Mek-Erk signaling pathway in a mammal of a compound selected from the group consisting of Wherein said physiological and / or pathophysiological condition is “malignant tumor, benign tumor, inflammatory disease, inflammation, pain, rheumatic disease, arthritic disease, HIV infection, neurological disease Or neurodegenerative diseases, rheumatism, arthritis, AIDS, ARC (AIDS-related syndrome), Kaposi's sarcoma, tumors derived from the brain and / or nervous system and / or meninges, dementia, Alzheimer's disease, hyperproliferative disease, psoriasis, uterus Endometriosis, scarring, benign prostatic hypertrophy (BPH), immune system disease, autoimmune disease, immunodeficiency disease, colon tumor, stomach tumor, intestinal tumor, lung tumor, pancreas 瘍, before prostate tumor, leukemia, melanoma, liver tumors, kidney tumor, head tumor, pharynx tumor, glioma, breast tumors, uterine cancer, endometrial cancer, cervical carcinoma, brain tumors, Sentoge astrocytoma , Bladder cancer, stomach tumor, colorectal tumor, esophageal cancer, gynecological tumor, ovarian tumor, thyroid cancer, lymphoma, chronic leukemia, acute leukemia, restenosis, diabetes, diabetic nephropathy, fibrosis, cystic fibrosis, Malignant nephrosclerosis, thrombotic microvascular syndrome, organ transplant rejection, glomerulopathy, metabolic disease, solid / fixed tumor, rheumatoid arthritis, diabetic retinopathy, asthma, allergy, allergic disease, chronic obstructive lung Disease, inflammatory bowel disease, fibrosis, atherosclerosis, heart disease, cardiovascular disease, myocardial disease, vascular disease, angiogenic disease, kidney disease, rhinitis, Graves' disease, local ischemia, heart failure , Ischemia, cardiac hypertrophy, renal failure, cardiomyocyte Failure, hypertension, vasoconstriction, stroke, anaphylactic shock, platelet aggregation, skeletal muscle atrophy, obesity, overweight, glucose homeostasis, congestive heart failure, angina, heart attack, myocardial infarction, hyperglycemia, hypoglycemia Said use selected from the group consisting of "hypertension".